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51. Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2

Author

Higgs, Martin R., Sato, Koichi, Reynolds, John J., Begum, Shabana, Bayley, Rachel, Goula, Amalia, Vernet, Audrey, Paquin, Karissa L., Skalnik, David G., Kobayashi, Wataru, Takata, Minoru, Howlett, Niall G., Kurumizaka, Hitoshi, Kimura, Hiroshi, and Stewart, Grant S.

Subjects
DNA Replication, replication stress, Fanconi Anemia Complementation Group D2 Protein, FANCD2, DNA, Histone-Lysine N-Methyltransferase, Methylation, Article, Epigenesis, Genetic, Nucleosomes, Histones, A549 Cells, SETD1A, Humans, Rad51 Recombinase, histone methylation, lysine methyltransferase, replication fork replication, BOD1L, HeLa Cells, Molecular Chaperones
Abstract

Summary Components of the Fanconi anemia and homologous recombination pathways play a vital role in protecting newly replicated DNA from uncontrolled nucleolytic degradation, safeguarding genome stability. Here we report that histone methylation by the lysine methyltransferase SETD1A is crucial for protecting stalled replication forks from deleterious resection. Depletion of SETD1A sensitizes cells to replication stress and leads to uncontrolled DNA2-dependent resection of damaged replication forks. The ability of SETD1A to prevent degradation of these structures is mediated by its ability to catalyze methylation on Lys4 of histone H3 (H3K4) at replication forks, which enhances FANCD2-dependent histone chaperone activity. Suppressing H3K4 methylation or expression of a chaperone-defective FANCD2 mutant leads to loss of RAD51 nucleofilament stability and severe nucleolytic degradation of replication forks. Our work identifies epigenetic modification and histone mobility as critical regulatory mechanisms in maintaining genome stability by restraining nucleases from irreparably damaging stalled replication forks., Graphical Abstract, Highlights • Methylation of H3K4 by SETD1A maintains genome stability during replication stress • SETD1A and H3K4 methylation stabilize RAD51 nucleofilaments to protect nascent DNA • SETD1A-dependent H3K4 methylation enhances FANCD2-dependent histone remodeling • Histone mobility stabilizes RAD51 nucleofilaments to inhibit fork degradation, Higgs et al. identify histone H3K4 methylation by SETD1A as essential to prevent genome instability during replication stress by enhancing FANCD2-dependent nucleosome remodeling. Loss of SETD1A or deficiencies in H3 mobilization by FANCD2 leads to RAD51 nucleofilament instability and severe nucleolytic degradation of stalled replication forks.

Published
2018

52. The APC/C and CBP/p300 cooperate to regulate transcription and cell-cycle progression

Author

Turnell, Andrew S., Stewart, Grant S., Grand, Roger J. A., Rookes, Susan M., Martin, Ashley, Yamano, Hiroyuki, Elledge, Stephen J., and Gallimore, Phillip H.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Andrew S. Turnell (corresponding author) [1]; Grant S. Stewart [1, 2]; Roger J. A. Grand [1]; Susan M. Rookes [1]; Ashley Martin [1]; Hiroyuki Yamano [3]; Stephen J. Elledge [...]

Published
2005
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54. MDC1 is a mediator of the mammalian DNA damage checkpoint

Author

Stewart, Grant S., Wang, Bin, Bignell, Colin R., Taylor, A. Malcolm R., and Elledge, Stephen J.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Grant S. Stewart [1]; Bin Wang [1]; Colin R. Bignell [2]; A. Malcolm R. Taylor [2]; Stephen J. Elledge (corresponding author) [1, 3, 4] To counteract the continuous exposure [...]

Published
2003
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61. The DNA double-strand break repair gene hMRE11 is mutated in individuals with an Ataxia-telangiectasia-like disorder

Author

Stewart, Grant S., Maser, Richard S., Stankovic, Tanja, Bressan, Debra A., Kaplan, Mark I., Jaspers, Nikolaas G.J., Raams, Anja, Byrd, Philip J., Petrini, John H.J., and Malcolm, R. Taylor

Subjects
Ataxia telangiectasia -- Genetic aspects, Brain diseases -- Physiological aspects, DNA damage -- Physiological aspects, Gene mutations -- Analysis, Biological sciences
Abstract

Results show that the molecular connection between double-strand break recognition by the protein complexes and cell's ability to activate ATM controlled DNA damage response pathway links hMre11 gene to the complex Ataxia-Telangiectasia disorder.

Published
1999

62. Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes

Author

Burrage, Lindsay C, Reynolds, John J, Baratang, Nissan Vida, Phillips, Jennifer B, Wegner, Jeremy, McFarquhar, Ashley, Higgs, Martin R, Christiansen, Audrey E, Lanza, Denise G, Seavitt, John R, Jain, Mahim, Li, Xiaohui, Parry, David A, Raman, Vandana, Chitayat, David, Chinn, Ivan K, Bertuch, Alison A, Karaviti, Lefkothea, Schlesinger, Alan E, Earl, Dawn, Bamshad, Michael, Savarirayan, Ravi, Doddapaneni, Harsha, Muzny, Donna, Jhangiani, Shalini N, Eng, Christine M, Gibbs, Richard A, Bi, Weimin, Emrick, Lisa, Rosenfeld, Jill A, Postlethwait, John, Westerfield, Monte, Dickinson, Mary E, Beaudet, Arthur L, Ranza, Emmanuelle, Huber, Celine, Cormier-Daire, Valérie, Shen, Wei, Mao, Rong, Heaney, Jason D, Orange, Jordan S, University of Washington Center for Mendelian Genomics, Undiagnosed Diseases Network, Bertola, Débora, Yamamoto, Guilherme L, Baratela, Wagner AR, Butler, Merlin G, Ali, Asim, Adeli, Mehdi, Cohn, Daniel H, Krakow, Deborah, Jackson, Andrew P, Lees, Melissa, Offiah, Amaka C, Carlston, Colleen M, Carey, John C, Stewart, Grant S, Bacino, Carlos A, Campeau, Philippe M, and Lee, Brendan

Subjects
Adult, Adolescent, Cells, Knockout, DNA repair, DNA replication, skeletal dysplasia, Osteochondrodysplasias, Medical and Health Sciences, SPONASTRIME dysplasia, Mice, Young Adult, TONSL, Rare Diseases, Clinical Research, Chromosomal Instability, Exome Sequencing, Genetics, Animals, Humans, 2.1 Biological and endogenous factors, Aetiology, University of Washington Center for Mendelian Genomics, Child, Preschool, Zebrafish, Alleles, Genetic Association Studies, Pediatric, Genetics & Heredity, Cultured, NF-kappa B, Genetic Variation, Undiagnosed Diseases Network, Fibroblasts, Biological Sciences, Musculoskeletal Abnormalities, Congenital Structural Anomalies, Female, DNA Damage
Abstract

SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessiveinheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl-/- murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl-/- zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.

Published
2019

63. Microarray analysis reveals that TP53- and ATM-mutant B-CLLs share a defect in activating proapoptotic responses after DNA damage but are distinguished by major differences in activating prosurvival responses

Author

Stankovic, Tatjana, Hubank, Mike, Cronin, Debbie, Stewart, Grant S., Fletcher, Danielle, Bignell, Colin R., Alvi, Azra J., Austen, Belinda, Weston, Victoria J., Fegan, Christopher, Byrd, Philip J., Moss, PaulA.H., and Taylor, A. Malcolm R.

Published
2004
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64. Chromosome instability syndromes

Author

Taylor, A.M.R., Rothblum-Oviatt, Cynthia, Ellis, Nathan A., Hickson, Ian D., Meyer, Stefan, Crawford, Thomas O., Weemaes, C.M.R., Stewart, Grant S., Taylor, A.M.R., Rothblum-Oviatt, Cynthia, Ellis, Nathan A., Hickson, Ian D., Meyer, Stefan, Crawford, Thomas O., Weemaes, C.M.R., and Stewart, Grant S.

Abstract

Item does not contain fulltext

Published
2019

65. Bi-allelic MCM10 mutations cause telomere shortening with immune dysfunction and cardiomyopathy

Author

Baxley, Ryan M., primary, Leung, Wendy, additional, Schmit, Megan M., additional, Matson, Jacob Peter, additional, Oram, Marissa K., additional, Wang, Liangjun, additional, Taylor, John, additional, Yin, Lulu, additional, Hedberg, Jack, additional, Rogers, Colette B., additional, Harvey, Adam J., additional, Basu, Debashree, additional, Taylor, Jenny C., additional, Pagnamenta, Alistair T., additional, Dreau, Helene, additional, Craft, Jude, additional, Ormondroyd, Elizabeth, additional, Watkins, Hugh, additional, Hendrickson, Eric A., additional, Mace, Emily M., additional, Orange, Jordan S., additional, Aihara, Hideki, additional, Stewart, Grant S., additional, Blair, Edward, additional, Cook, Jeanette Gowen, additional, and Bielinsky, Anja-Katrin, additional

Published
2019
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68. Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia

Author

Chang, Hae Ryung, primary, Cho, Sung Yoon, additional, Lee, Jae Hoon, additional, Lee, Eunkyung, additional, Seo, Jieun, additional, Lee, Hye Ran, additional, Cavalcanti, Denise P., additional, Mäkitie, Outi, additional, Valta, Helena, additional, Girisha, Katta M., additional, Lee, Chung, additional, Neethukrishna, Kausthubham, additional, Bhavani, Gandham S., additional, Shukla, Anju, additional, Nampoothiri, Sheela, additional, Phadke, Shubha R., additional, Park, Mi Jung, additional, Ikegawa, Shiro, additional, Wang, Zheng, additional, Higgs, Martin R., additional, Stewart, Grant S., additional, Jung, Eunyoung, additional, Lee, Myeong-Sok, additional, Park, Jong Hoon, additional, Lee, Eun A., additional, Kim, Hongtae, additional, Myung, Kyungjae, additional, Jeon, Woosung, additional, Lee, Kyoungyeul, additional, Kim, Dongsup, additional, Kim, Ok-Hwa, additional, Choi, Murim, additional, Lee, Han-Woong, additional, Kim, Yonghwan, additional, and Cho, Tae-Joon, additional

Published
2019
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69. Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes

Author

Burrage, Lindsay C., primary, Reynolds, John J., additional, Baratang, Nissan Vida, additional, Phillips, Jennifer B., additional, Wegner, Jeremy, additional, McFarquhar, Ashley, additional, Higgs, Martin R., additional, Christiansen, Audrey E., additional, Lanza, Denise G., additional, Seavitt, John R., additional, Jain, Mahim, additional, Li, Xiaohui, additional, Parry, David A., additional, Raman, Vandana, additional, Chitayat, David, additional, Chinn, Ivan K., additional, Bertuch, Alison A., additional, Karaviti, Lefkothea, additional, Schlesinger, Alan E., additional, Earl, Dawn, additional, Bamshad, Michael, additional, Savarirayan, Ravi, additional, Doddapaneni, Harsha, additional, Muzny, Donna, additional, Jhangiani, Shalini N., additional, Eng, Christine M., additional, Gibbs, Richard A., additional, Bi, Weimin, additional, Emrick, Lisa, additional, Rosenfeld, Jill A., additional, Postlethwait, John, additional, Westerfield, Monte, additional, Dickinson, Mary E., additional, Beaudet, Arthur L., additional, Ranza, Emmanuelle, additional, Huber, Celine, additional, Cormier-Daire, Valérie, additional, Shen, Wei, additional, Mao, Rong, additional, Heaney, Jason D., additional, Orange, Jordan S., additional, Bertola, Débora, additional, Yamamoto, Guilherme L., additional, Baratela, Wagner A.R., additional, Butler, Merlin G., additional, Ali, Asim, additional, Adeli, Mehdi, additional, Cohn, Daniel H., additional, Krakow, Deborah, additional, Jackson, Andrew P., additional, Lees, Melissa, additional, Offiah, Amaka C., additional, Carlston, Colleen M., additional, Carey, John C., additional, Stewart, Grant S., additional, Bacino, Carlos A., additional, Campeau, Philippe M., additional, Lee, Brendan, additional, Adams, David R., additional, Aday, Aaron, additional, Alejandro, Mercedes E., additional, Allard, Patrick, additional, Ashley, Euan A., additional, Azamian, Mahshid S., additional, Baker, Eva, additional, Balasubramanyam, Ashok, additional, Barseghyan, Hayk, additional, Batzli, Gabriel F., additional, Beggs, Alan H., additional, Behnam, Babak, additional, Bellen, Hugo J., additional, Bernstein, Jonathan A., additional, Berry, Gerard T., additional, Bican, Anna, additional, Bick, David P., additional, Birch, Camille L., additional, Bonner, Devon, additional, Boone, Braden E., additional, Bostwick, Bret L., additional, Briere, Lauren C., additional, Brokamp, Elly, additional, Brown, Donna M., additional, Brush, Matthew, additional, Burke, Elizabeth A., additional, Burrage, Lindsay C., additional, Butte, Manish J., additional, Chen, Shan, additional, Clark, Gary D., additional, Coakley, Terra R., additional, Cogan, Joy D., additional, Colley, Heather A., additional, Cooper, Cynthia M., additional, Cope, Heidi, additional, Craigen, William J., additional, D’Souza, Precilla, additional, Davids, Mariska, additional, Davidson, Jean M., additional, Dayal, Jyoti G., additional, Dell’Angelica, Esteban C., additional, Dhar, Shweta U., additional, Dipple, Katrina M., additional, Donnell-Fink, Laurel A., additional, Dorrani, Naghmeh, additional, Dorset, Daniel C., additional, Douine, Emilie D., additional, Draper, David D., additional, Dries, Annika M., additional, Duncan, Laura, additional, Eckstein, David J., additional, Emrick, Lisa T., additional, Enns, Gregory M., additional, Eskin, Ascia, additional, Esteves, Cecilia, additional, Estwick, Tyra, additional, Fernandez, Liliana, additional, Ferreira, Carlos, additional, Fieg, Elizabeth L., additional, Fisher, Paul G., additional, Fogel, Brent L., additional, Friedman, Noah D., additional, Gahl, William A., additional, Glanton, Emily, additional, Godfrey, Rena A., additional, Goldman, Alica M., additional, Goldstein, David B., additional, Gould, Sarah E., additional, Gourdine, Jean-Philippe F., additional, Groden, Catherine A., additional, Gropman, Andrea L., additional, Haendel, Melissa, additional, Hamid, Rizwan, additional, Hanchard, Neil A., additional, High, Frances, additional, Holm, Ingrid A., additional, Hom, Jason, additional, Howerton, Ellen M., additional, Huang, Yong, additional, Jamal, Fariha, additional, Jiang, Yong-hui, additional, Johnston, Jean M., additional, Jones, Angela L., additional, Koeller, David M., additional, Kohane, Isaac S., additional, Kohler, Jennefer N., additional, Krasnewich, Donna M., additional, Korrick, Susan, additional, Koziura, Mary, additional, Krier, Joel B., additional, Kyle, Jennifer E., additional, Lalani, Seema R., additional, Lau, C. Christopher, additional, Lazar, Jozef, additional, LeBlanc, Kimberly, additional, Lee, Brendan H., additional, Lee, Hane, additional, Levy, Shawn E., additional, Lewis, Richard A., additional, Lincoln, Sharyn A., additional, Loo, Sandra K., additional, Loscalzo, Joseph, additional, Maas, Richard L., additional, Macnamara, Ellen F., additional, MacRae, Calum A., additional, Maduro, Valerie V., additional, Majcherska, Marta M., additional, Malicdan, May Christine V., additional, Mamounas, Laura A., additional, Manolio, Teri A., additional, Markello, Thomas C., additional, Marom, Ronit, additional, Martin, Martin G., additional, Martínez-Agosto, Julian A., additional, Marwaha, Shruti, additional, May, Thomas, additional, McConkie-Rosell, Allyn, additional, McCormack, Colleen E., additional, McCray, Alexa T., additional, Merker, Jason D., additional, Metz, Thomas O., additional, Might, Matthew, additional, Moretti, Paolo M., additional, Morimoto, Marie, additional, Mulvihill, John J., additional, Murdock, David R., additional, Murphy, Jennifer L., additional, Muzny, Donna M., additional, Nehrebecky, Michele E., additional, Nelson, Stan F., additional, Newberry, J. Scott, additional, Newman, John H., additional, Nicholas, Sarah K., additional, Novacic, Donna, additional, Orengo, James P., additional, Pallais, J. Carl, additional, Palmer, Christina G.S., additional, Papp, Jeanette C., additional, Parker, Neil H., additional, Pena, Loren D.M., additional, Phillips, John A., additional, Posey, Jennifer E., additional, Postlethwait, John H., additional, Potocki, Lorraine, additional, Pusey, Barbara N., additional, Renteria, Genecee, additional, Reuter, Chloe M., additional, Rives, Lynette, additional, Robertson, Amy K., additional, Rodan, Lance H., additional, Sampson, Jacinda B., additional, Samson, Susan L., additional, Schoch, Kelly, additional, Scott, Daryl A., additional, Shakachite, Lisa, additional, Sharma, Prashant, additional, Shashi, Vandana, additional, Signer, Rebecca, additional, Silverman, Edwin K., additional, Sinsheimer, Janet S., additional, Smith, Kevin S., additional, Spillmann, Rebecca C., additional, Stoler, Joan M., additional, Stong, Nicholas, additional, Sullivan, Jennifer A., additional, Sweetser, David A., additional, Tan, Queenie K.-G., additional, Tifft, Cynthia J., additional, Toro, Camilo, additional, Tran, Alyssa A., additional, Urv, Tiina K., additional, Vilain, Eric, additional, Vogel, Tiphanie P., additional, Waggott, Daryl M., additional, Wahl, Colleen E., additional, Walley, Nicole M., additional, Walsh, Chris A., additional, Walker, Melissa, additional, Wan, Jijun, additional, Wangler, Michael F., additional, Ward, Patricia A., additional, Waters, Katrina M., additional, Webb-Robertson, Bobbie-Jo M., additional, Wheeler, Matthew T., additional, Wise, Anastasia L., additional, Wolfe, Lynne A., additional, Worthey, Elizabeth A., additional, Yamamoto, Shinya, additional, Yang, John, additional, Yang, Yaping, additional, Yoon, Amanda J., additional, Yu, Guoyun, additional, Zastrow, Diane B., additional, Zhao, Chunli, additional, and Zheng, Allison, additional

Published
2019
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70. PALB2 variant status in hematological malignancies – a potential therapeutic target?

Author

Oldreive, Ceri E., primary, Byrd, Philip J., additional, Stewart, Grant S., additional, Taylor, Alexander J., additional, Farhat, Sana, additional, Skowronska, Anna, additional, Smith, Edward, additional, Raghavan, Manoj, additional, Janic, Dragana, additional, Dokmanovic, Lidija, additional, Clokie, Sam, additional, Davies, Nicholas, additional, Kwok, Marwan, additional, Pratt, Guy, additional, Paneesha, Shankara, additional, Moss, Paul, additional, Stankovic, Tatjana, additional, and Taylor, Malcolm, additional

Published
2019
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72. Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2

Author

30281728, Higgs, Martin R., Sato, Koichi, Reynolds, John J., Begum, Shabana, Bayley, Rachel, Goula, Amalia, Vernet, Audrey, Paquin, Karissa L., Skalnik, David G., Kobayashi, Wataru, Takata, Minoru, Howlett, Niall G., Kurumizaka, Hitoshi, Kimura, Hiroshi, Stewart, Grant S., 30281728, Higgs, Martin R., Sato, Koichi, Reynolds, John J., Begum, Shabana, Bayley, Rachel, Goula, Amalia, Vernet, Audrey, Paquin, Karissa L., Skalnik, David G., Kobayashi, Wataru, Takata, Minoru, Howlett, Niall G., Kurumizaka, Hitoshi, Kimura, Hiroshi, and Stewart, Grant S.

Abstract

Components of the Fanconi anemia and homologous recombination pathways play a vital role in protecting newly replicated DNA from uncontrolled nucleolytic degradation, safeguarding genome stability. Here we report that histone methylation by the lysine methyltransferase SETD1A is crucial for protecting stalled replication forks from deleterious resection. Depletion of SETD1A sensitizes cells to replication stress and leads to uncontrolled DNA2-dependent resection of damaged replication forks. The ability of SETD1A to prevent degradation of these structures is mediated by its ability to catalyze methylation on Lys4 of histone H3 (H3K4) at replication forks, which enhances FANCD2-dependent histone chaperone activity. Suppressing H3K4 methylation or expression of a chaperone-defective FANCD2 mutant leads to loss of RAD51 nucleofilament stability and severe nucleolytic degradation of replication forks. Our work identifies epigenetic modification and histone mobility as critical regulatory mechanisms in maintaining genome stability by restraining nucleases from irreparably damaging stalled replication forks.

Published
2018

75. PIN1 isomerisation of BRCA1 promotes replication fork protection

Author

Daza-Martin, Manuel, primary, Jamshad, Mohammed, additional, Starowicz, Katarzyna, additional, Chauhan, Anoop Singh, additional, Beesley, James F.J., additional, Coles, Jennifer L., additional, Stewart, Grant S., additional, Densham, Ruth M., additional, and Morris, Joanna R., additional

Published
2018
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76. MYBL2 Supports DNA Double Strand Break Repair in Hematopoietic Stem Cells

Author

Bayley, Rachel, primary, Blakemore, Daniel, additional, Cancian, Laila, additional, Dumon, Stephanie, additional, Volpe, Giacomo, additional, Ward, Carl, additional, Almaghrabi, Ruba, additional, Gujar, Jidnyasa, additional, Reeve, Natasha, additional, Raghavan, Manoj, additional, Higgs, Martin R., additional, Stewart, Grant S., additional, Petermann, Eva, additional, and García, Paloma, additional

Published
2018
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77. Analysis of novel missense ATR mutations reveals new splicing defects underlying Seckel syndrome

Author

Llorens-Agost, Marta, primary, Luessing, Janna, additional, van Beneden, Amandine, additional, Eykelenboom, John, additional, O'Reilly, Dawn, additional, Bicknell, Louise S, additional, Reynolds, John J, additional, van Koegelenberg, Marianne, additional, Hurles, Matthew E, additional, Brady, Angela F, additional, Jackson, Andrew P, additional, Stewart, Grant S, additional, and Lowndes, Noel F, additional

Published
2018
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78. Degradation of a Novel DNA Damage Response Protein, Tankyrase 1 Binding Protein 1, following Adenovirus Infection

Author

Chalabi Hagkarim, Nafiseh, primary, Ryan, Ellis L., additional, Byrd, Philip J., additional, Hollingworth, Robert, additional, Shimwell, Neil J., additional, Agathanggelou, Angelo, additional, Vavasseur, Manon, additional, Kolbe, Viktoria, additional, Speiseder, Thomas, additional, Dobner, Thomas, additional, Stewart, Grant S., additional, and Grand, Roger J., additional

Published
2018
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80. Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

Author

Reynolds, John J., Bicknell, Louise S., Carroll, Paula, Higgs, Martin R., Shaheen, Ranad, Murray, Jennie E., Papadopoulos, Dimitrios K., Leitch, Andrea, Murina, Olga, Tarnauskaite, Zygimante, Wessel, Sarah R., Zlatanou, Anastasia, Vernet, Audrey, von Kriegsheim, Alex, Mottram, Rachel M. A., Logan, Clare V., Bye, Hannah, Li, Yun, Brean, Alexander, Maddirevula, Sateesh, Challis, Rachel C., Skouloudaki, Kassiani, Almoisheer, Agaadir, Alsaif, Hessa S., Amar, Ariella, Prescott, Natalie J., Bober, Michael B., Duker, Angela, Faqeih, Eissa, Seidahmed, Mohammed Zain, Al Tala, Saeed, Alswaid, Abdulrahman, Ahmed, Saleem, Al-Aama, Jumana Yousuf, Altmueller, Janine, Al Balwi, Mohammed, Brady, Angela F., Chessa, Luciana, Cox, Helen, Fischetto, Rita, Heller, Raoul, Henderson, Bertram D., Hobson, Emma, Nurnberg, Peter, Percin, E. Ferda, Peron, Angela, Spaccini, Luigina, Quigley, Alan J., Thakur, Seema, Wise, Carol A., Yoon, Grace, Alnemer, Maha, Tomancak, Pavel, Yigit, Goekhan, Taylor, A. Malcolm R., Reijns, Martin A. M., Simpson, Michael A., Cortez, David, Alkuraya, Fowzan S., Mathew, Christopher G., Jackson, Andrew P., Stewart, Grant S., Reynolds, John J., Bicknell, Louise S., Carroll, Paula, Higgs, Martin R., Shaheen, Ranad, Murray, Jennie E., Papadopoulos, Dimitrios K., Leitch, Andrea, Murina, Olga, Tarnauskaite, Zygimante, Wessel, Sarah R., Zlatanou, Anastasia, Vernet, Audrey, von Kriegsheim, Alex, Mottram, Rachel M. A., Logan, Clare V., Bye, Hannah, Li, Yun, Brean, Alexander, Maddirevula, Sateesh, Challis, Rachel C., Skouloudaki, Kassiani, Almoisheer, Agaadir, Alsaif, Hessa S., Amar, Ariella, Prescott, Natalie J., Bober, Michael B., Duker, Angela, Faqeih, Eissa, Seidahmed, Mohammed Zain, Al Tala, Saeed, Alswaid, Abdulrahman, Ahmed, Saleem, Al-Aama, Jumana Yousuf, Altmueller, Janine, Al Balwi, Mohammed, Brady, Angela F., Chessa, Luciana, Cox, Helen, Fischetto, Rita, Heller, Raoul, Henderson, Bertram D., Hobson, Emma, Nurnberg, Peter, Percin, E. Ferda, Peron, Angela, Spaccini, Luigina, Quigley, Alan J., Thakur, Seema, Wise, Carol A., Yoon, Grace, Alnemer, Maha, Tomancak, Pavel, Yigit, Goekhan, Taylor, A. Malcolm R., Reijns, Martin A. M., Simpson, Michael A., Cortez, David, Alkuraya, Fowzan S., Mathew, Christopher G., Jackson, Andrew P., and Stewart, Grant S.

Abstract

To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.

Published
2017

81. A hypomorphic PALB2 allele gives rise to an unusual form of FA-N associated with lymphoid tumour development

Author

McKinnon, Peter, Byrd, Philip J, Stewart, Grant. S, Smith, Anna, Eaton, Charlotte, Taylor, Alexander J, Guy, Chloe, Eringyte, Ieva, Fooks, Peggy, Last, James I, Horsley, Robert, Oliver, Antony W, Janic, Dragana, Dokmanovic, Lidija, Stankovic, Tatjana, and Taylor, A Malcolm R

Subjects
Q1
Abstract

Patients with biallelic truncating mutations in PALB2 have a severe form of Fanconi anaemia (FA-N), with a predisposition for developing embryonal-type tumours in infancy. Here we describe two unusual patients from a single family, carrying biallelic PALB2 mutations, one truncating, c.1676_1677delAAinsG;(p.Gln559ArgfsTer2), and the second, c.2586+1G>A; p.Thr839_Lys862del resulting in an in frame skip of exon 6 (24 amino acids). Strikingly, the affected individuals did not exhibit the severe developmental defects typical of FA-N patients and initially presented with B cell non-Hodgkin lymphoma. The expressed p.Thr839_Lys862del mutant PALB2 protein retained the ability to interact with BRCA2, previously unreported in FA-N patients. There was also a large increased chromosomal radiosensitivity following irradiation in G2 and increased sensitivity to mitomycin C. Although patient cells were unable to form Rad51 foci following exposure to either DNA damaging agent, U2OS cells, in which the mutant PALB2 with in frame skip of exon 6 was induced, did show recruitment of Rad51 to foci following damage. We conclude that a very mild form of FA-N exists arising from a hypomorphic PALB2 allele.

Published
2016

84. A Novel Role of PALB2 in Lymphoid Tumour Development

Author

Stankovic, Tatjana, primary, Byrd, Philip J, additional, Stewart, Grant S, additional, Taylor, Alexander J, additional, Smith, Anna, additional, Fooks, Peggy, additional, Horsley, Robert, additional, Last, James I, additional, Janic, Dragana, additional, Dokmanovic, Lidija, additional, Oliver, Antony W, additional, and Taylor, A.Malcolm R, additional

Published
2016
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86. Targeting the Ataxia Telangiectasia Mutated-null Phenotype in Chronic Lymphocytic Leukemia with Pro-oxidants

Author

Agathanggelou, Angelo, Weston, Victoria J., Perry, Tracey, Davies, Nicholas J., Skowronska, Anna, Payne, Daniel T., Fossey, John S., Oldreive, Ceri E., Wei, Wenbin, Pratt, Guy, Parry, Helen, Oscier, David, Coles, Steve J., Hole, Paul S., Darley, Richard L., McMahon, Michael, Hayes, John D., Moss, Paul, Stewart, Grant S., Taylor, A. Malcolm R., and Stankovic, Tatjana

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Gene Expression Regulation, Leukemic, NF-E2-Related Factor 2, Homozygote, Apoptosis, Articles, Ataxia Telangiectasia Mutated Proteins, Oxidants, Response Elements, Leukemia, Lymphocytic, Chronic, B-Cell, Xenograft Model Antitumor Assays, Antioxidants, Mitochondria, RC0254, Disease Models, Animal, Phenotype, Superoxides, Caspases, Mutation, Animals, Humans, Tumor Suppressor Protein p53, Reactive Oxygen Species, Protein Binding
Abstract

Inactivation of the Ataxia Telangiectasia Mutated gene in chronic lymphocytic leukemia results in resistance to p53-dependent apoptosis and inferior responses to treatment with DNA damaging agents. Hence, p53-independent strategies are required to target Ataxia\ud Telangiectasia Mutated-deficient chronic lymphocytic leukemia. As Ataxia Telangiectasia Mutated has been implicated in redox homeostasis, we investigated the effect of the Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia genotype on cellular responses to\ud oxidative stress with a view to therapeutic targeting. We found that in comparison to Ataxia Telangiectasia Mutated-wild type chronic lymphocytic leukemia, pro-oxidant treatment of Ataxia Telangiectasia Mutated-null cells led to reduced binding of NF-E2 p45-related factor-2 to antioxidant response elements and thus decreased expression of target genes. Furthermore, Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia cells contained lower levels of antioxidants and elevated mitochondrial reactive oxygen species. Consequently, Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia, but not tumours with 11q deletion or TP53 mutations, exhibited differentially increased sensitivity to pro-oxidants both in vitro and in vivo. We found that cell death was mediated by a p53- and caspase-independent mechanism associated with apoptosis inducing factor activity. Together, these data suggest that defective redox-homeostasis represents an attractive therapeutic target for Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia.

Published
2015

87. TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism

Author

Harley, Margaret E., Murina, Olga, Leitch, Andrea, Higgs, Martin R., Bicknell, Louise S., Yigit, Goekhan, Blackford, Andrew N., Zlatanou, Anastasia, Mackenzie, Karen J., Reddy, Kaalak, Halachev, Mihail, McGlasson, Sarah, Reijns, Martin A. M., Fluteau, Adeline, Martin, Carol-Anne, Sabbioneda, Simone, Elcioglu, Nursel H., Altmueller, Janine, Thiele, Holger, Greenhalgh, Lynn, Chessa, Luciana, Maghnie, Mohamad, Salim, Mahmoud, Bober, Michael B., Nuernberg, Peter, Jackson, Stephen P., Hurles, Matthew E., Wollnik, Bernd, Stewart, Grant S., Jackson, Andrew P., Harley, Margaret E., Murina, Olga, Leitch, Andrea, Higgs, Martin R., Bicknell, Louise S., Yigit, Goekhan, Blackford, Andrew N., Zlatanou, Anastasia, Mackenzie, Karen J., Reddy, Kaalak, Halachev, Mihail, McGlasson, Sarah, Reijns, Martin A. M., Fluteau, Adeline, Martin, Carol-Anne, Sabbioneda, Simone, Elcioglu, Nursel H., Altmueller, Janine, Thiele, Holger, Greenhalgh, Lynn, Chessa, Luciana, Maghnie, Mohamad, Salim, Mahmoud, Bober, Michael B., Nuernberg, Peter, Jackson, Stephen P., Hurles, Matthew E., Wollnik, Bernd, Stewart, Grant S., and Jackson, Andrew P.

Abstract

DNA lesions encountered by replicative polymerases threaten genome stability and cell cycle progression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism. We establish that TRAIP relocalizes to sites of DNA damage, where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to ultraviolet (UV) irradiation, as well as fork progression through UV-induced DNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP therefore limit cellular proliferation, providing a potential mechanism for microcephaly and dwarfism phenotypes. Human genetics thus identifies TRAIP as a component of the DNA damage response to replication-blocking DNA lesions.

Published
2016

88. BRCA2 and RAD51 promote double-strand break formation and cell death in response to Gemcitabine

Author

Jones, Rebecca M., Kotsantis, Panagiotis, Stewart, Grant S., Groth, Petra, and Petermann, Eva

Subjects
BRCA2 Protein, DNA Replication, Antimetabolites, Antineoplastic, Cell Death, Cell Survival, Deoxycytidine, Gemcitabine, Article, enzymes and coenzymes (carbohydrates), Neoplasms, MCF-7 Cells, Humans, DNA Breaks, Double-Stranded, Rad51 Recombinase
Abstract

Replication inhibitors cause replication fork stalling and double-strand breaks (DSB) that result from processing of stalled forks. During recovery from replication blocks, the homologous recombination (HR) factor RAD51 mediates fork restart and DSB repair. HR defects therefore sensitize cells to replication inhibitors, with clear implications for cancer therapy. Gemcitabine is a potent replication inhibitor used to treat cancers with mutations in HR genes such as BRCA2. Here, we investigate why, paradoxically, mutations in HR genes protect cells from killing by gemcitabine. Using DNA replication and DNA damage assays in mammalian cells, we show that even short gemcitabine treatments cause persistent replication inhibition. BRCA2 and RAD51 are recruited to chromatin early after removal of the drug, actively inhibit replication fork progression, and promote the formation of MUS81- and XPF-dependent DSBs that remain unrepaired. Our data suggest that HR intermediates formed at gemcitabine-stalled forks are converted into DSBs and thus contribute to gemcitabine-induced cell death, which could have implications for the treatment response of HR-deficient tumors.

Published
2014

89. RNF168 and USP10 regulate topoisomerase IIα function via opposing effects on its ubiquitylation

Author

Guturi, Kiran Kumar Naidu, primary, Bohgaki, Miyuki, additional, Bohgaki, Toshiyuki, additional, Srikumar, Tharan, additional, Ng, Deborah, additional, Kumareswaran, Ramya, additional, El Ghamrasni, Samah, additional, Jeon, Justin, additional, Patel, Parasvi, additional, Eldin, Mohamed Saad, additional, Bristow, Rob, additional, Cheung, Peter, additional, Stewart, Grant S., additional, Raught, Brian, additional, Hakem, Anne, additional, and Hakem, Razqallah, additional

Published
2016
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90. A Hypomorphic PALB2 Allele Gives Rise to an Unusual Form of FA-N Associated with Lymphoid Tumour Development

Author

Byrd, Philip J., primary, Stewart, Grant. S., additional, Smith, Anna, additional, Eaton, Charlotte, additional, Taylor, Alexander J., additional, Guy, Chloe, additional, Eringyte, Ieva, additional, Fooks, Peggy, additional, Last, James I., additional, Horsley, Robert, additional, Oliver, Antony W., additional, Janic, Dragana, additional, Dokmanovic, Lidija, additional, Stankovic, Tatjana, additional, and Taylor, A. Malcolm R., additional

Published
2016
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92. TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism

Author

Harley, Margaret E, primary, Murina, Olga, additional, Leitch, Andrea, additional, Higgs, Martin R, additional, Bicknell, Louise S, additional, Yigit, Gökhan, additional, Blackford, Andrew N, additional, Zlatanou, Anastasia, additional, Mackenzie, Karen J, additional, Reddy, Kaalak, additional, Halachev, Mihail, additional, McGlasson, Sarah, additional, Reijns, Martin A M, additional, Fluteau, Adeline, additional, Martin, Carol-Anne, additional, Sabbioneda, Simone, additional, Elcioglu, Nursel H, additional, Altmüller, Janine, additional, Thiele, Holger, additional, Greenhalgh, Lynn, additional, Chessa, Luciana, additional, Maghnie, Mohamad, additional, Salim, Mahmoud, additional, Bober, Michael B, additional, Nürnberg, Peter, additional, Jackson, Stephen P, additional, Hurles, Matthew E, additional, Wollnik, Bernd, additional, Stewart, Grant S, additional, and Jackson, Andrew P, additional

Published
2015
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94. BOD1L Is Required to Suppress Deleterious Resection of Stressed Replication Forks

Author

Higgs, Martin R., primary, Reynolds, John J., additional, Winczura, Alicja, additional, Blackford, Andrew N., additional, Borel, Valérie, additional, Miller, Edward S., additional, Zlatanou, Anastasia, additional, Nieminuszczy, Jadwiga, additional, Ryan, Ellis L., additional, Davies, Nicholas J., additional, Stankovic, Tatjana, additional, Boulton, Simon J., additional, Niedzwiedz, Wojciech, additional, and Stewart, Grant S., additional

Published
2015
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97. Mutations in the NHEJ Component XRCC4 Cause Primordial Dwarfism

Author

Murray, Jennie E., primary, van der Burg, Mirjam, additional, IJspeert, Hanna, additional, Carroll, Paula, additional, Wu, Qian, additional, Ochi, Takashi, additional, Leitch, Andrea, additional, Miller, Edward S., additional, Kysela, Boris, additional, Jawad, Alireza, additional, Bottani, Armand, additional, Brancati, Francesco, additional, Cappa, Marco, additional, Cormier-Daire, Valerie, additional, Deshpande, Charu, additional, Faqeih, Eissa A., additional, Graham, Gail E., additional, Ranza, Emmanuelle, additional, Blundell, Tom L., additional, Jackson, Andrew P., additional, Stewart, Grant S., additional, and Bicknell, Louise S., additional

Published
2015
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99. Identification of the First ATRIP–Deficient Patient and Novel Mutations in ATR Define a Clinical Spectrum for ATR–ATRIP Seckel Syndrome

Author

Ogi, Tomoo, Walker, Sarah, Stiff, Tom, Hobson, Emma, Limsirichaikul, Siripan, Carpenter, Gillian, Prescott, Katrina, Suri, Mohnish, Byrd, Philip J., Matsuse, Michiko, Mitsutake, Norisato, Nakazawa, Yuka, Vasudevan, Pradeep, Barrow, Margaret, Stewart, Grant S., Taylor, A. Malcolm R., O'Driscoll, Mark, Jeggo, Penny A., Ogi, Tomoo, Walker, Sarah, Stiff, Tom, Hobson, Emma, Limsirichaikul, Siripan, Carpenter, Gillian, Prescott, Katrina, Suri, Mohnish, Byrd, Philip J., Matsuse, Michiko, Mitsutake, Norisato, Nakazawa, Yuka, Vasudevan, Pradeep, Barrow, Margaret, Stewart, Grant S., Taylor, A. Malcolm R., O'Driscoll, Mark, and Jeggo, Penny A.

Abstract

A homozygous mutational change in the Ataxia-Telangiectasia and RAD3 related (ATR) gene was previously reported in two related families displaying Seckel Syndrome (SS). Here, we provide the first identification of a Seckel Syndrome patient with mutations in ATRIP, the gene encoding ATR-Interacting Protein (ATRIP), the partner protein of ATR required for ATR stability and recruitment to the site of DNA damage. The patient has compound heterozygous mutations in ATRIP resulting in reduced ATRIP and ATR expression. A nonsense mutational change in one ATRIP allele results in a C-terminal truncated protein, which impairs ATR-ATRIP interaction; the other allele is abnormally spliced. We additionally describe two further unrelated patients native to the UK with the same novel, heterozygous mutations in ATR, which cause dramatically reduced ATR expression. All patient-derived cells showed defective DNA damage responses that can be attributed to impaired ATR-ATRIP function. Seckel Syndrome is characterised by microcephaly and growth delay, features also displayed by several related disorders including Majewski (microcephalic) osteodysplastic primordial dwarfism (MOPD) type II and Meier-Gorlin Syndrome (MGS). The identification of an ATRIP-deficient patient provides a novel genetic defect for Seckel Syndrome. Coupled with the identification of further ATR-deficient patients, our findings allow a spectrum of clinical features that can be ascribed to the ATR-ATRIP deficient sub-class of Seckel Syndrome. ATR-ATRIP patients are characterised by extremely severe microcephaly and growth delay, microtia (small ears), micrognathia (small and receding chin), and dental crowding. While aberrant bone development was mild in the original ATR-SS patient, some of the patients described here display skeletal abnormalities including, in one patient, small patellae, a feature characteristically observed in Meier-Gorlin Syndrome. Collectively, our analysis exposes an overlapping clinical manife, PLoS Genetics, 8(11), e1002945; 2012

Published
2012

100. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage

Author

Stewart, Grant S., Panier, Stephanie, Townsend, Kelly, Al-Hakim, Abdallah K., Kolas, Nadine K., Miller, Edward S., Nakada, Shinichiro, Ylanko, Jarkko, Olivarius, Signe, Mendez, Megan, Oldreive, Ceri, Wildenhain, Jan, Tagliaferro, Andrea, Pelletier, Laurence, Taubenheim, Nadine, Durandy, Anne, Byrd, Philip J., Stankovic, Tatjana, Taylor, A. Malcolm R., Durocher, Daniel, Stewart, Grant S., Panier, Stephanie, Townsend, Kelly, Al-Hakim, Abdallah K., Kolas, Nadine K., Miller, Edward S., Nakada, Shinichiro, Ylanko, Jarkko, Olivarius, Signe, Mendez, Megan, Oldreive, Ceri, Wildenhain, Jan, Tagliaferro, Andrea, Pelletier, Laurence, Taubenheim, Nadine, Durandy, Anne, Byrd, Philip J., Stankovic, Tatjana, Taylor, A. Malcolm R., and Durocher, Daniel

Abstract

Udgivelsesdato: Feb 6, The biological response to DNA double-strand breaks acts to preserve genome integrity. Individuals bearing inactivating mutations in components of this response exhibit clinical symptoms that include cellular radiosensitivity, immunodeficiency, and cancer predisposition. The archetype for such disorders is Ataxia-Telangiectasia caused by biallelic mutation in ATM, a central component of the DNA damage response. Here, we report that the ubiquitin ligase RNF168 is mutated in the RIDDLE syndrome, a recently discovered immunodeficiency and radiosensitivity disorder. We show that RNF168 is recruited to sites of DNA damage by binding to ubiquitylated histone H2A. RNF168 acts with UBC13 to amplify the RNF8-dependent histone ubiquitylation by targeting H2A-type histones and by promoting the formation of lysine 63-linked ubiquitin conjugates. These RNF168-dependent chromatin modifications orchestrate the accumulation of 53BP1 and BRCA1 to DNA lesions, and their loss is the likely cause of the cellular and developmental phenotypes associated with RIDDLE syndrome.

Published
2009

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