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1. Independent and sequential recruitment of NHEJ and HR factors to DNA damage sites in mammalian cells

Author

Kim, Jong-Soo, Krasieva, Tatiana B, Kurumizaka, Hitoshi, Chen, David J, Taylor, A Malcolm R, and Yokomori, Kyoko

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, Underpinning research, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Aetiology, Generic health relevance, Acid Anhydride Hydrolases, Animals, Antigens, Nuclear, Ataxia Telangiectasia Mutated Proteins, Cell Cycle, Cell Cycle Proteins, Cell Line, Checkpoint Kinase 2, Chromosomal Proteins, Non-Histone, DNA Damage, DNA Repair, DNA Repair Enzymes, DNA-Binding Proteins, Fungal Proteins, Histones, Humans, Ku Autoantigen, Lasers, MRE11 Homologue Protein, Mice, Mice, Knockout, Nuclear Proteins, Phosphorylation, Protein Serine-Threonine Kinases, Protein Transport, Recombination, Genetic, Signal Transduction, Tumor Suppressor Proteins, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Damage recognition by repair/checkpoint factors is the critical first step of the DNA damage response. DNA double strand breaks (DSBs) activate checkpoint signaling and are repaired by nonhomologous end-joining (NHEJ) and homologous recombination (HR) pathways. However, in vivo kinetics of the individual factor responses and the mechanism of pathway choice are not well understood. We report cell cycle and time course analyses of checkpoint activation by ataxia-telangiectasia mutated and damage site recruitment of the repair factors in response to laser-induced DSBs. We found that MRN acts as a DNA damage marker, continuously localizing at unrepaired damage sites. Damage recognition by NHEJ factors precedes that of HR factors. HR factor recruitment is not influenced by NHEJ factor assembly and occurs throughout interphase. Damage site retention of NHEJ factors is transient, whereas HR factors persist at unrepaired lesions, revealing unique roles of the two pathways in mammalian cells.

Published
2005

2. Chromosome instability syndromes

Author

Taylor, A. Malcolm R., Rothblum-Oviatt, Cynthia, Ellis, Nathan A., Hickson, Ian D., Meyer, Stefan, Crawford, Thomas O., Smogorzewska, Agata, Pietrucha, Barbara, Weemaes, Corry, and Stewart, Grant S.

Published
2019
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3. 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, Tarnauskaitė, Žygimantė, 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, Altmüller, Janine, Al Balwi, Mohammed, Brady, Angela F, Chessa, Luciana, Cox, Helen, Fischetto, Rita, Heller, Raoul, Henderson, Bertram D, Hobson, Emma, Nürnberg, Peter, Percin, E Ferda, Peron, Angela, Spaccini, Luigina, Quigley, Alan J, Thakur, Seema, Wise, Carol A, Yoon, Grace, Alnemer, Maha, Tomancak, Pavel, Yigit, Gökhan, 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

Published
2017
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7. Childhood-Onset Movement Disorders Can Mask a Primary Immunodeficiency: 6 Cases of Classical Ataxia-Telangiectasia and Variant Forms

Author

Blanchard-Rohner, Geraldine, primary, Peirolo, Anna, additional, Coulon, Ludivine, additional, Korff, Christian, additional, Horvath, Judit, additional, Burkhard, Pierre R., additional, Gumy-Pause, Fabienne, additional, Ranza, Emmanuelle, additional, Jandus, Peter, additional, Dibra, Harpreet, additional, Taylor, Alexander Malcolm R., additional, and Fluss, Joel, additional

Published
2022
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8. Hypomorphic PCNA mutation underlies a human DNA repair disorder

Author

Baple, Emma L., Chambers, Helen, Cross, Harold E., Fawcett, Heather, Nakazawa, Yuka, Chioza, Barry A., Harlalka, Gaurav V., Mansour, Sahar, Sreekantan-Nair, Ajith, Patton, Michael A., Muggenthaler, Martina, Rich, Phillip, Wagner, Karin, Coblentz, Roselyn, Stein, Constance K., Last, James I., Taylor, A. Malcolm R., Jackson, Andrew P., Ogi, Tomoo, Lehmann, Alan R., Green, Catherine M., and Crosby, Andrew H.

Subjects
Gene mutations -- Identification and classification, DNA repair -- Research, Genetic research, Nervous system -- Degeneration, Health care industry
Abstract

Numerous human disorders, including Cockayne syndrome, UV-sensitive syndrome, xeroderma pigmentosum, and trichothiodystrophy, result from the mutation of genes encoding molecules important for nucleotide excision repair. Here, we describe a syndrome in which the cardinal clinical features include short stature, hearing loss, premature aging, telangiectasia, neurodegeneration, and photosensitivity, resulting from a homozygous missense (p.Ser228Ile) sequence alteration of the proliferating cell nuclear antigen (PCNA). PCNA is a highly conserved sliding clamp protein essential for DNA replication and repair. Due to this fundamental role, mutations in PCNA that profoundly impair protein function would be incompatible with life. Interestingly, while the p.Ser228Ile alteration appeared to have no effect on protein levels or DNA replication, patient cells exhibited marked abnormalities in response to UV irradiation, displaying substantial reductions in both UV survival and RNA synthesis recovery. The p.Ser228Ile change also profoundly altered PCNA's interaction with Flap endonuclease 1 and DNA Ligase 1, DNA metabolism enzymes. Together, our findings detail a mutation of PCNA in humans associated with a neurodegenerative phenotype, displaying clinical and molecular features common to other DNA repair disorders, which we showed to be attributable to a hypomorphic amino acid alteration., Introduction Maintenance of genomic integrity is fundamentally important for normal cell division and basic cellular biological processes. The molecular characterization of human DNA damage sensitivity disorders, such as ataxia telangiectasia [...]

Published
2014
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12. Genomic profiling of acute myeloid leukaemia associated with ataxia telangiectasia identifies a complex karyotype with wild-type TP53 and mutant KRAS, G3BP1 and IL7R

Author

Goldgraben, Mae A, Fewings, Eleanor, Larionov, Alexey, Scarth, James, Redman, James, Telford, Nick, Arkwright, Peter D, Bonney, Denise, Wilks, Deepti, Kulkarni, Samar, Taylor, A Malcolm R, Tischkowitz, Marc D, Meyer, Stefan, Goldgraben, Mae A [0000-0002-1111-2804], Meyer, Stefan [0000-0002-2283-3690], and Apollo - University of Cambridge Repository

Subjects
Chromosome Aberrations, Adolescent, Gene Expression Profiling, DNA Helicases, Ataxia Telangiectasia Mutated Proteins, Polymorphism, Single Nucleotide, Interleukin-7 Receptor alpha Subunit, Proto-Oncogene Proteins p21(ras), Ataxia Telangiectasia, Leukemia, Myeloid, Acute, RNA Recognition Motif Proteins, Humans, Female, Tumor Suppressor Protein p53, Poly-ADP-Ribose Binding Proteins, Transcriptome, RNA Helicases
Abstract

Ataxia Telangiectasia (A-T) is an autosomal recessive disease, characterised by progressive neurodegeneration with cerebellar ataxia, oculo-cutaneous telangiectasia, immunodeficiency and cancer predisposition. It is caused by biallelic mutations in ATM (Ataxia Telangiectasia Mutated, chromosome 11q22.3) encoding a serine/threonine kinase essential in cell cycle control, DNA double-strand break repair and haematopoietic stem cell maintenance 1,2. Individuals with A-T classically develop lymphoid malignancies, a broad spectrum of other malignancies 3 and rarely, acute myeloid leukaemia (AML) 4-7. Previous AT-AML reports have described the karyotype and dismall clinical course (Supplementray Table S1). We performed sequential sample genomic profiling of an AML that developed in a 17-year-old female with A-T, to identify secondary genetic events towards myeloid malignancy (full clinical case history in Supplementary Information).

Published
2020

14. Autosomal recessive spinocerebellar ataxia and peripheral neuropathy with raised [alpha]-fetoprotein

Author

Izatt, Louise, Nemeth, Andrea H., Meesaq, Anjela, Mills, Kerry R., Taylor, A. Malcolm R., and Shaw, Christopher E.

Subjects
Spinocerebellar ataxia -- Development and progression, Spinocerebellar ataxia -- Research, Spinocerebellar ataxia -- Genetic aspects, Polyneuropathies -- Development and progression, Polyneuropathies -- Research, Polyneuropathies -- Genetic aspects, Alpha fetoproteins -- Research, Health
Abstract

Byline: Louise Izatt (5), Andrea H. Nemeth (1), Anjela Meesaq (1), Kerry R. Mills (2), A. Malcolm R. Taylor (3), Christopher E. Shaw (4) Keywords: spinocerebellar ataxia; raised AFP; peripheral neuropathy; autosomal recessive; ataxia telangiectasia variant Abstract: Abstract. We describe three patients from two families with progressive spinocerebellar ataxia, peripheral neuropathy, raised [alpha]-fetoprotein (AFP) and hypercholesterolaemia. Two siblings had identical clinical features, with late childhood onset of symptoms and slow progression, requiring crutches to walk at ages 37 and 38 years. Another patient developed ataxia aged 13 years and became wheel-chair bound by 20 years of age. Although they all had raised serum AFP levels, their clinical, immunological, biochemical, cytogenetic and molecular genetic studies failed to support a diagnosis of Ataxia Telangiectasia. Extensive investigation including imaging, biochemical and genetic studies excluded other known ataxias. Their clinical features most closely resemble the phenotype of a single consanguineous Japanese family with four individuals affected by spinocerebellar ataxia, peripheral neuropathy, raised AFP and hypercholesterolaemia. Homozygosity mapping has identified a locus in this Japanese family at 9q34. Haplotype analysis of our cases demonstrated possible linkage to 9q34, suggesting these may be the first Caucasian families described with this disorder. Author Affiliation: (1) Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, UK (2) Department of Neurophysiology, Guy's, King's and St Thomas' School of Medicine and King's College Hospital, Denmark Hill Campus, London SE5 9RS, UK (3) CRC Institute for Cancer Studies Vincent Drive, University of Birmingham, Edgbaston Birmingham, B15 2TT, UK (4) Department of Neurology Academic Neurosciences Building, King's College Hospital, Kings Denmark Hill Campus, Denmark Hill, London SE5 9RS, UK (5) Department of Clinical Genetics, Guy's and St Thomas' Hospital NHS Trust, St Thomas Street, London SE1 9RT, UK Article History: Registration Date: 01/01/2004 Received Date: 13/08/2003 Accepted Date: 18/01/2004

Published
2004

15. 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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17. Genomic profiling of acute myeloid leukaemia associated with ataxia telangiectasia identifies a complex karyotype with wild‐type TP53 and mutant KRAS, G3BP1 and IL7R

Author

Goldgraben, Mae A., primary, Fewings, Eleanor, additional, Larionov, Alexey, additional, Scarth, James, additional, Redman, James, additional, Telford, Nick, additional, Arkwright, Peter D., additional, Bonney, Denise, additional, Wilks, Deepti, additional, Kulkarni, Samar, additional, Taylor, A. Malcolm R., additional, Tischkowitz, Marc D., additional, and Meyer, Stefan, additional

Published
2020
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18. Integrative analysis of spontaneous CLL regression highlights genetic and microenvironmental interdependency in CLL

Author

Kwok, Marwan, primary, Oldreive, Ceri, additional, Rawstron, Andy C., additional, Goel, Anshita, additional, Papatzikas, Grigorios, additional, Jones, Rhiannon E., additional, Drennan, Samantha, additional, Agathanggelou, Angelo, additional, Sharma-Oates, Archana, additional, Evans, Paul, additional, Smith, Edward, additional, Dalal, Surita, additional, Mao, Jingwen, additional, Hollows, Robert, additional, Gordon, Naheema, additional, Hamada, Mayumi, additional, Davies, Nicholas J., additional, Parry, Helen, additional, Beggs, Andrew D., additional, Munir, Talha, additional, Moreton, Paul, additional, Paneesha, Shankara, additional, Pratt, Guy, additional, Taylor, A. Malcolm R., additional, Forconi, Francesco, additional, Baird, Duncan M., additional, Cazier, Jean-Baptiste, additional, Moss, Paul, additional, Hillmen, Peter, additional, and Stankovic, Tatjana, additional

Published
2020
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21. Dynamic changes in clonal cytogenetic architecture during progression of chronic lymphocytic leukemia in patients and patient-derived murine xenografts

Author

Davies, Nicholas J., Kwok, Marwan, Gould, Clive, Oldreive, Ceri E., Mao, Jingwen, Parry, Helen, Smith, Edward, Agathanggelou, Angelo, Pratt, Guy, Taylor, Alexander Malcolm R., Moss, Paul, Griffiths, Mike, and Stankovic, Tatjana

Subjects
Chromosome Aberrations, Male, clonal evolution, Prognosis, Research Papers, Combined Modality Therapy, Leukemia, Lymphocytic, Chronic, B-Cell, cytogenetics, Disease Models, Animal, Mice, Treatment Outcome, hemic and lymphatic diseases, Karyotyping, multiplexed-FISH, Disease Progression, chronic lymphocytic leukemia, Animals, Heterografts, Humans, Female, xenograft, Single-Cell Analysis, In Situ Hybridization, Fluorescence
Abstract

Subclonal heterogeneity and clonal selection influences disease progression in chronic lymphocytic leukemia (CLL). It is therefore important that therapeutic decisions are made based on an understanding of the CLL clonal architecture and its dynamics in individual patients. Identification of cytogenetic abnormalities by FISH remains the cornerstone of contemporary clinical practice and provides a simple means for prognostic stratification. Here, we demonstrate that multiplexed-FISH can enhance recognition of CLL subclonal repertoire and its dynamics during disease progression, both in patients and CLL patient-derived xenografts (PDX). We applied a combination of patient-specific FISH probes to 24 CLL cases before treatment and at relapse, and determined putative ancestral relationships between subpopulations with different cytogenetic features. We subsequently established 7 CLL PDX models in NOD/Shi-SCID/IL-2Rγctm1sug/Jic (NOG) mice. Application of multiplexed-FISH to these models demonstrated that all of the identified cytogenetic subpopulations had leukemia propagating activity and that changes in their representation during disease progression could be spontaneous, accelerated by treatment or treatment-induced. We conclude that multiplexed-FISH in combination with PDX models have the potential to distinguish between spontaneous and treatment-induced clonal selection, and therefore provide a valuable tool for the pre-clinical evaluation of novel therapies.

Published
2017

25. 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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26. A single ataxia telangiectasia gene with a product similar to Pl-3 kinase

Author

Savitsky, Kinneret, Bar-Shira, Anat, Gilad, Shlomit, Rotman, Galit, Ziv, Yael, Vanagaite, Lina, Tagle, Danilo A., Smith, Sara, Uziel, Tamar, Sfez, Sharon, Ashkenazi, Maya, Pecker, Iris, Frydman, Moshe, Harnik, Reli, Patanjali, Sankhavaram R., Simmons, Andrew, Clines, Gregory A., Sartiel, Adam, Gatti, Richard A., Chessa, Luciana, Sanal, Ozden, Lavin, Martin F., Jaspers, N.G.J., Taylor, A. Malcolm R., Arlett, Colin F., Miki, Toru, Weissman, Sherman M., Lovett, Michael, Collins, Francis, and Shiloh, Yosef

Subjects
Ataxia telangiectasia -- Genetic aspects, Cancer -- Genetic aspects, Science and technology, Genetic aspects
Abstract

A gene, ATM, that is mutated in the autosomal recessive disorder ataxia telangiectasia (AT) was identified by positional cloning on chromosome 11q22-23. AT is characterized by cerebellar degeneration, immunodeficiency, chromosomal instability, cancer predisposition, radiation sensitivity, and cell cycle abnormalities. The disease is genetically heterogeneous, with four complementation groups that have been suspected to represent different genes. ATM, which has a transcript of 12 kilobases, was found to be mutated in AT patients from all complementation groups, indicating that it is probably the sole gene responsible for this disorder. A partial ATM complementary DNA clone of 5.9 kilobases encoded a putative protein that is similar to several yeast and mammalian phosphati-dylinositol-3' kinases that are involved in mitogenic signal transduction, meiotic recombination, and cell cycle control. The discovery of ATM should enhance understanding of AT and related syndromes and may allow the identification of AT heterozygotes, who are at increased risk of cancer., Ataxia telangiectasia is inherited in a monogenic, autosomal recessive manner, with a worldwide incidence of 1 in 40,000 to 1 in 100,000 [1]. Ataxia telangiectasia is usually first noticed in [...]

Published
1995

29. 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

30. 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

31. USP7 inhibition alters homologous recombination repair and targets CLL cells independently of ATM/p53 functional status

Author

Agathanggelou, Angelo, primary, Smith, Edward, additional, Davies, Nicholas J., additional, Kwok, Marwan, additional, Zlatanou, Anastasia, additional, Oldreive, Ceri E., additional, Mao, Jingwen, additional, Da Costa, David, additional, Yadollahi, Sina, additional, Perry, Tracey, additional, Kearns, Pamela, additional, Skowronska, Anna, additional, Yates, Elliot, additional, Parry, Helen, additional, Hillmen, Peter, additional, Reverdy, Celine, additional, Delansorne, Remi, additional, Paneesha, Shankara, additional, Pratt, Guy, additional, Moss, Paul, additional, Taylor, A. Malcolm R., additional, Stewart, Grant S., additional, and Stankovic, Tatjana, additional

Published
2017
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32. 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

34. Hypomorphic PCNA mutation underlies a novel human DNA repair disorder

Author

Baple, Emma L, Chambers, Helen, Cross, Harold E, Fawcett, Heather, Nakazawa, Yuka, Chioza, Barry A, Harlalka, Gaurav V, Mansour, Sahar, Sreekantan-Nair, Ajith, Patton, Michael A, Muggenthaler, Martina, Rich, Phillip, Wagner, Karin, Coblentz, Roselyn, Stein, Constance K, Last, James I, Taylor, A Malcolm R, Jackson, Andrew P, Ogi, Tomoo, Lehmann, Alan R, Green, Catherine M, and Crosby, Andrew H

Subjects
RB155.5
Abstract

A number of human disorders, including Cockayne syndrome, UV-sensitive syndrome, xeroderma pigmentosum and trichothiodystrophy, result from the mutation of genes encoding molecules important for nucleotide excision repair. Here, we describe a novel syndrome in which the cardinal clinical features include postnatal growth retardation, hearing loss, premature aging, telangiectasia, neurological signs and photosensitivity, resulting from a homozygous missense (p.Ser228Ile) sequence alteration of the proliferating cell nuclear antigen (PCNA). PCNA is a highly conserved sliding clamp protein essential for DNA replication and repair. Due to this fundamental role, mutations in PCNA that profoundly impair protein function would be incompatible with life. Interestingly, while the p.Ser228Ile alteration appears to have no effect on protein levels or DNA replication, patient cells exhibit significant abnormalities in response to UV irradiation displaying substantial reductions in both UV survival and RNA synthesis recovery. The p.Ser228Ile change also profoundly alters PCNA’s interaction with Flap endonuclease 1 and DNA Ligase 1, DNA metabolism enzymes. Taken together our findings detail the first mutation of PCNA in humans, associated with a unique neurodegenerative disease displaying clinical and molecular features common to other DNA repair disorders, which we show to be attributable to a hypomorphic amino acid alteration.

Published
2014

36. 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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38. T-cell number and subtype influence the disease course of primary chronic lymphocytic leukaemia xenografts in alymphoid mice

Author

Oldreive, Ceri E., primary, Skowronska, Anna, additional, Davies, Nicholas J., additional, Parry, Helen, additional, Agathanggelou, Angelo, additional, Krysov, Sergey, additional, Packham, Graham, additional, Rudzki, Zbigniew, additional, Cronin, Laura, additional, Vrzalikova, Katerina, additional, Murray, Paul, additional, Odintsova, Elena, additional, Pratt, Guy, additional, Taylor, A. Malcolm R., additional, Moss, Paul, additional, and Stankovic, Tatjana, additional

Published
2015
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42. 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

43. A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3)

Author

Enciso-Mora, Victor, Broderick, Peter, Ma, Yussanne, Jarrett, Ruth F, Hjalgrim, Henrik, Hemminki, Kari, Van Den Berg, Anke, Olver, Bianca, Lloyd, Amy, Dobbins, Sara E., Lightfoot, Tracy, van Leeuwen, Flora E, Försti, Asta, Diepstra, Arjan, Broeks, Annegien, Vijayakrishnan, Jayaram, Shield, Lesley, Lake, Annette, Montgomery, Dorothy, Roman, Eve, Engert, Andreas, Von Strandmann, Elke Pogge, Reiners, Katrin S., Nolte, Ilja M, Smedby, Karin E, Adami, Hans-Olov, Russell, Nicola S, Glimelius, Bengt, Hamilton-Dutoit, Stephen, De Bruin, Marieke, Ryder, Lars P., Molin, Daniel G. M., Sorensen, Karina Meden, Chang, Ellen T., Taylor, A. Malcolm R., Cooke, Rosie, Hofstra, Robert, Westers, Helga, Van Wezel, Tom, Van Eijk, Ronald, Ashworth, Alan, Rostgaard, Klaus, Melbye, Mads, Swerdlow, Anthony J, Houlston, Richard S, Enciso-Mora, Victor, Broderick, Peter, Ma, Yussanne, Jarrett, Ruth F, Hjalgrim, Henrik, Hemminki, Kari, Van Den Berg, Anke, Olver, Bianca, Lloyd, Amy, Dobbins, Sara E., Lightfoot, Tracy, van Leeuwen, Flora E, Försti, Asta, Diepstra, Arjan, Broeks, Annegien, Vijayakrishnan, Jayaram, Shield, Lesley, Lake, Annette, Montgomery, Dorothy, Roman, Eve, Engert, Andreas, Von Strandmann, Elke Pogge, Reiners, Katrin S., Nolte, Ilja M, Smedby, Karin E, Adami, Hans-Olov, Russell, Nicola S, Glimelius, Bengt, Hamilton-Dutoit, Stephen, De Bruin, Marieke, Ryder, Lars P., Molin, Daniel G. M., Sorensen, Karina Meden, Chang, Ellen T., Taylor, A. Malcolm R., Cooke, Rosie, Hofstra, Robert, Westers, Helga, Van Wezel, Tom, Van Eijk, Ronald, Ashworth, Alan, Rostgaard, Klaus, Melbye, Mads, Swerdlow, Anthony J, and Houlston, Richard S

Abstract

To identify susceptibility loci for classical Hodgkin's lymphoma (cHL), we conducted a genome-wide association study of 589 individuals with cHL (cases) and 5,199 controls with validation in four independent samples totaling 2,057 cases and 3,416 controls. We identified three new susceptibility loci at 2p16.1 (rs1432295, REL, odds ratio (OR) = 1.22, combined P = 1.91 × 10 -8), 8q24.21 (rs2019960, PVT1, OR = 1.33, combined P = 1.26 × 10-13) and 10p14 (rs501764, GATA3, OR = 1.25, combined P = 7.05 × 10-8). Furthermore, we confirmed the role of the major histocompatibility complex in disease etiology by revealing a strong human leukocyte antigen (HLA) association (rs6903608, OR = 1.70, combined P = 2.84 × 10 -50). These data provide new insight into the pathogenesis of cHL.

Published
2010

44. 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

45. Biallelic ATM Inactivation Significantly Reduces Survival in Patients Treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 Trial

Author

Skowronska, Anna, primary, Parker, Anton, additional, Ahmed, Gulshanara, additional, Oldreive, Ceri, additional, Davis, Zadie, additional, Richards, Sue, additional, Dyer, Martin, additional, Matutes, Estella, additional, Gonzalez, David, additional, Taylor, A. Malcolm R., additional, Moss, Paul, additional, Thomas, Peter, additional, Oscier, David, additional, and Stankovic, Tatjana, additional

Published
2012
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47. Identification of the First ATRIP–Deficient Patient and Novel Mutations in ATR Define a Clinical Spectrum for ATR–ATRIP Seckel Syndrome

Author

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

Published
2012
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48. Regulation of DNA-End Resection by hnRNPU-like Proteins Promotes DNA Double-Strand Break Signaling and Repair

Author

Polo, Sophie E., primary, Blackford, Andrew N., additional, Chapman, J. Ross, additional, Baskcomb, Linda, additional, Gravel, Serge, additional, Rusch, Andre, additional, Thomas, Anoushka, additional, Blundred, Rachel, additional, Smith, Philippa, additional, Kzhyshkowska, Julia, additional, Dobner, Thomas, additional, Taylor, A. Malcolm R., additional, Turnell, Andrew S., additional, Stewart, Grant S., additional, Grand, Roger J., additional, and Jackson, Stephen P., additional

Published
2012
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50. Biallelic ATM Inactivation Significantly Reduces Survival in Chronic Lymphocytic Leukemia Patients Treated with Alkylating Agent/Purine Analogue Therapy: Results From the UKCLL4 Trial

Author

Skowronska, Anna, primary, Ahmed, Gulshanara, additional, Oldreive, Ceri E, additional, Oscier, David, additional, Parker, Anton, additional, Dyer, Martin J.S., additional, Matutes, Estella, additional, Taylor, A. Malcolm R, additional, Moss, Paul AH, additional, and Stankovic, Tatjana, additional

Published
2011
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