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1. Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy

Author

Grange, Laura J., Reynolds, John J., Ullah, Farid, Isidor, Bertrand, Shearer, Robert F., Latypova, Xenia, Baxley, Ryan M., Oliver, Antony W., Ganesh, Anil, Cooke, Sophie L., Jhujh, Satpal S., McNee, Gavin S., Hollingworth, Robert, Higgs, Martin R., Natsume, Toyoaki, Khan, Tahir, Martos-Moreno, Gabriel Á., Chupp, Sharon, Mathew, Christopher G., Parry, David, Simpson, Michael A., Nahavandi, Nahid, Yüksel, Zafer, Drasdo, Mojgan, Kron, Anja, Vogt, Petra, Jonasson, Annemarie, Seth, Saad Ahmed, Gonzaga-Jauregui, Claudia, Brigatti, Karlla W., Stegmann, Alexander P. A., Kanemaki, Masato, Josifova, Dragana, Uchiyama, Yuri, Oh, Yukiko, Morimoto, Akira, Osaka, Hitoshi, Ammous, Zineb, Argente, Jesús, Matsumoto, Naomichi, Stumpel, Constance T.R.M., Taylor, Alexander M. R., Jackson, Andrew P., Bielinsky, Anja-Katrin, Mailand, Niels, Le Caignec, Cedric, Davis, Erica E., and Stewart, Grant S.

Published
2022
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2. Activation and modulation of the DNA damage response during lytic replication of Kaposi's sarcoma-associated herpesvirus

Author

Hollingworth, Robert

Subjects
616.99, QH301 Biology, QH426 Genetics, RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of several human malignancies. Herpesviruses are known to modulate cellular pathways responsible for the recognition and repair of DNA lesions, collectively known as the DNA damage response (DDR). Here it is demonstrated that lytic reactivation of KSHV in B cells results in activation of the ATM and DNA-PK kinases that regulate the response to DNA double-strand breaks (DSBs). This DDR does not depend on amplification of viral DNA and results in phosphorylation of downstream proteins involved in DNA repair, cell cycle regulation and apoptosis. Specific inhibition of ATM activity attenuates KSHV replication while, in contrast, abrogation of DNA-PK activity enhances amplification of viral DNA. It is also shown here that cells containing lytic virus enter S phase which is required for efficient viral replication and robust activation of the DDR. In addition, immunofluorescence microscopy reveals that DNA damage sensing proteins such as MRE11 and Ku80 localise to sites of KSHV replication while other DSB repair proteins form foci in cellular DNA. Specific inhibition of MRE11 exonuclease activity in B cells restricts KSHV replication efficiency indicating that this DDR protein contributes positively to this phase of the viral lifecycle.

Published
2017

4. RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1

Author

Abu-Libdeh, Bassam, Jhujh, Satpal S., Dhar, Srijita, Sommers, Joshua A., Datta, Arindam, Longo, Gabriel M.C., Grange, Laura J., Reynolds, John J., Cooke, Sophie L., McNee, Gavin S., Hollingworth, Robert, Woodward, Beth L., Ganesh, Anil N., Smerdon, Stephen J., Nicolae, Claudia M., Durlacher-Betzer, Karina, Molho-Pessach, Vered, Abu-Libdeh, Abdulsalam, Meiner, Vardiella, Moldovan, George-Lucian, Roukos, Vassilis, Harel, Tamar, Brosh, Robert M., Jr., and Stewart, Grant S.

Subjects
Gene mutations -- Research, Genetic disorders -- Causes of, Medical research, Medicine, Experimental, DNA -- Structure -- Health aspects, Helicases -- Health aspects -- Genetic aspects, Health care industry
Abstract

Despite being the first homolog of the bacterial RecQ helicase to be identified in humans, the function of RECQL1 remains poorly characterized. Furthermore, unlike other members of the human RECQ family of helicases, mutations in RECQL1 have not been associated with a genetic disease. Here, we identify 2 families with a genome instability disorder that we have named RECON (RECql ONe) syndrome, caused by biallelic mutations in the RECQL gene. The affected individuals had short stature, progeroid facial features, a hypoplastic nose, xeroderma, and skin photosensitivity and were homozygous for the same missense mutation in RECQL1 (p.Ala459Ser), located within its zinc binding domain. Biochemical analysis of the mutant RECQL1 protein revealed that the p.A459S missense mutation compromised its ATPase, helicase, and fork restoration activity, while its capacity to promote single-strand DNA annealing was largely unaffected. At the cellular level, this mutation in RECQL1 gave rise to a defect in the ability to repair DNA damage induced by exposure to topoisomerase poisons and a failure of DNA replication to progress efficiently in the presence of abortive topoisomerase lesions. Taken together, RECQL1 is the fourth member of the RecQ family of helicases to be associated with a human genome instability disorder., Introduction DNA helicases are ubiquitous enzymes found in most uni- and multicellular organisms and function to unwind DNA in an ATP-dependent and direction-specific manner. The ability to unwind DNA is [...]

Published
2022
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6. Rapid evolution meets invasive species control: the potential for pesticide resistance in sea lamprey

Author

Dunlop, Erin S., McLaughlin, Rob, Adams, Jean V., Jones, Michael, Birceanu, Oana, Christie, Mark R., Criger, Lori A., Hinderer, Julia L.M., Hollingworth, Robert M., Johnson, Nicholas S., Lantz, Stephen R., Li, Weiming, Miller, James, Morrison, Bruce J., Mota-Sanchez, David, Muir, Andrew, Sepulveda, Maria S., Steeves, Todd, Walter, Lisa, Westman, Erin, Wirgin, Isaac, and Wilkie, Michael P.

Subjects
Introduced species -- Physiological aspects -- Observations, Pesticide resistance -- Observations, Sea lamprey -- Physiological aspects -- Observations, Earth sciences
Abstract

Rapid evolution of pest, pathogen, and wildlife populations can have undesirable effects, for example, when insects evolve resistance to pesticides or fishes evolve smaller body size in response to harvest. A destructive invasive species in the Laurentian Great Lakes, the sea lamprey (Petromyzon marinus) has been controlled with the pesticide 3-trifluoromethyl-4-nitrophenol (TFM) since the 1950s. We evaluated the likelihood of sea lamprey evolving resistance to TFM by (i) reviewing sea lamprey life history and control; (ii) identifying physiological and behavioural resistance strategies; (iii) estimating the strength of selection from TFM; (iv) assessing the timeline for evolution; and (v) analyzing historical toxicity data for evidence of resistance. The number of sea lamprey generations exposed to TFM was within the range observed for fish populations where rapid evolution has occurred. Mortality from TFM was estimated as 82%-90%, suggesting significant selective pressure. However, 57 years of toxicity data revealed no increase in lethal concentrations of TFM. Vigilance and the development of alternative controls are required to prevent this aquatic invasive species from evolving strategies to evade control. Resume : L'evolution rapide de populations d'organismes nuisibles, de pathogenes et d'animaux sauvages peut avoir des effets indesirables comme, par exemple, des insectes qui developpent une resistance aux pesticides ou une diminution de la taille du corps des poissons en reponse a la peche. Le pesticide 3-trifluoromethyl-4-nitrophenol (TFM) est utilise depuis les annees 1950 pour lutter contre la lamproie (Petromyzon marinus), une espece envahissante destructrice dans les Grands Lacs laurentiens. Nous avons evalue la probabilite que les lamproies developpent une resistance au TFM par (i) l'examen du cycle biologique des lamproies et des methodes de lutte contre cette espece, (ii) la determination des strategies de resistance physiologiques et comportementales (iii) l'estimation de la force de la selection decoulant du TFM, (iv) revaluation de la duree necessaire pour qu'il y ait evolution et (v) l'analyse de donnees historiques sur la toxicite pour voir s'il existe des indices de resistance. Le nombre de generations de lamproies exposees au TFM est dans la fourchette observee pour les populations de poissons ayant subi une evolution rapide. La mortalite causee par le TFM est estimee a 82-90 %, ce qui indiquerait une pression de selection significative. Cependant, 57 annees de donnees sur la toxicite ne revelent aucune augmentation des concentrations letales de TFM. La vigilance et la mise au point d'autres mesures de lutte sont necessaries pour empecher cette espece aquatique envahissante de developper des strategies lui permettant de contrer les efforts de lutte. [Traduit par la Redaction], Introduction The capability of pathogens and pests to evolve resistance to control measures is a global concern with implications for human health, natural resource management, and agriculture (Palumbi 2001). Resistance [...]

Published
2018
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7. Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy

Author

Grange, Laura J, Reynolds, John J, Ullah, Farid, Isidor, Bertrand, Shearer, Robert F, Latypova, Xenia, Baxley, Ryan M, Oliver, Antony W, Ganesh, Anil, Cooke, Sophie L, Jhujh, Satpal S, McNee, Gavin S, Hollingworth, Robert, Higgs, Martin R, Natsume, Toyoaki, Khan, Tahir, Martos-Moreno, Gabriel Á., Chupp, Sharon, Mathew, Christopher G., Parry, David, Simpson, Michael A., Nahavandi, Nahid, Yüksel, Zafer, Drasdo, Mojgan, Kron, Anja, Vogt, Petra, Jonasson, Annemarie, Seth, Saad Ahmed, Gonzaga-Jauregui, Claudia, Brigatti, Karlla W, Stegmann, Alexander P A, Kanemaki, Masato, Josifova, Dragana, Uchiyama, Yuri, Oh, Yukiko, Morimoto, Akira, Osaka, Hitoshi, Ammous, Zineb, Argente, Jesús, Matsumoto, Naomichi, Stumpel, Constance T.R.M., Taylor, Alexander M.R., Jackson, Andrew P., Bielinsky, Anja-Katrin, Mailand, Niels, Le Caignec, Cedric, Davis, Erica E., Stewart, Grant S., Grange, Laura J, Reynolds, John J, Ullah, Farid, Isidor, Bertrand, Shearer, Robert F, Latypova, Xenia, Baxley, Ryan M, Oliver, Antony W, Ganesh, Anil, Cooke, Sophie L, Jhujh, Satpal S, McNee, Gavin S, Hollingworth, Robert, Higgs, Martin R, Natsume, Toyoaki, Khan, Tahir, Martos-Moreno, Gabriel Á., Chupp, Sharon, Mathew, Christopher G., Parry, David, Simpson, Michael A., Nahavandi, Nahid, Yüksel, Zafer, Drasdo, Mojgan, Kron, Anja, Vogt, Petra, Jonasson, Annemarie, Seth, Saad Ahmed, Gonzaga-Jauregui, Claudia, Brigatti, Karlla W, Stegmann, Alexander P A, Kanemaki, Masato, Josifova, Dragana, Uchiyama, Yuri, Oh, Yukiko, Morimoto, Akira, Osaka, Hitoshi, Ammous, Zineb, Argente, Jesús, Matsumoto, Naomichi, Stumpel, Constance T.R.M., Taylor, Alexander M.R., Jackson, Andrew P., Bielinsky, Anja-Katrin, Mailand, Niels, Le Caignec, Cedric, Davis, Erica E., and Stewart, Grant S.

Abstract

Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.

Published
2022

10. A Degenerate PCNA-Interacting Peptide (DPIP) box targets RNF168 to replicating DNA to limit 53BP1 signaling

Author

Yang, Yang, primary, Jayaprakash, Deepika, additional, Hollingworth, Robert, additional, Chen, Steve, additional, Jablonski, Amy E., additional, Gao, Yanzhe, additional, Anand, Jay Ramanlal, additional, Mutter-Rottmayer, Elizabeth, additional, An, Jing, additional, Cheng, Xing, additional, Pearce, Kenneth H., additional, Blanchet, Sophie-Anne, additional, Fradet-Turcotte, Amélie, additional, Stewart, Grant S., additional, and Vaziri, Cyrus, additional

Published
2021
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16. Contributors to the Handbook

Author

Acre, Gail, primary, Adgate, John L., additional, Ames, Bruce N., additional, Balakrishman, Sharada, additional, Barnett, Margot, additional, Baynes, Ronald E., additional, Billington, Richard, additional, Blondell, Jerome M., additional, Boone, J. Scott, additional, Breathnach, Ruaidhri, additional, Breckenridge, Charles B., additional, Brooks, Gerald T., additional, Brouwer, Derk H., additional, Bui, Quang, additional, Calvert, Geoffrey M., additional, Carlock, Linda L., additional, Carmichael, Neal, additional, Carr, Russell L., additional, Chambers, Howard W., additional, Chambers, Janice E., additional, Chester, Graham, additional, Clark, J. Marshall, additional, Clarkson, Thomas, additional, Class, Thomas, additional, Cochran, Roger C., additional, Dayan, Franck E., additional, de Cock, Johan S., additional, Dix, Kelly J., additional, Dong, Michael, additional, Dotson, Timothy A., additional, Doull, John, additional, Driver, Jeffrey H., additional, Duke, Stephen O., additional, Eastmond, David A., additional, Ecobichon, Donald J., additional, Ehrich, Marion, additional, Eisenbrandt, David L., additional, Eldridge, J. Charles, additional, Evans, Jeffrey B., additional, Farmer, Donna, additional, Crisp, Pennelope A. Fenner-, additional, Fujita, Toshio, additional, Gammon, Derek W., additional, Garry, V.F., additional, Glynn, Paul, additional, Gollapudi, B.B., additional, Goodman, Gay, additional, Gordon, Elliot B., additional, Hanley, Thomas R., additional, Harp, Paul, additional, Harris, Jane E., additional, Hayes, Wayland J., additional, Hershberger, Leon W., additional, Hertner, Thomas, additional, Hess, Frederick G., additional, Heydens, William F., additional, Hodgson, Ernest, additional, Hollingworth, Robert M., additional, Hurt, Susan, additional, Iyer, Poorni R., additional, Jackson, Richard J., additional, Johnson, Martin K., additional, Jortner, Bernard S., additional, Kaneko, Hideo, additional, Kavlock, Robert J., additional, Kenna, Michael P., additional, Kennepohl, Elke, additional, Krieger, William C., additional, Lamb, Ian C., additional, Lampman, Richard L., additional, Levi, Patricia E., additional, Lyubimov, A.V., additional, Liu, Jing, additional, Lock, Edward A., additional, Lotti, Marcello, additional, Lunchik, Curt, additional, Maibach, Howard I., additional, Manley, Neela B., additional, Mannala, Shajan, additional, Marsh, Rex E., additional, McCahon, Peter, additional, McGeehin, Michael, additional, Mehler, Louise N., additional, Miyamoto, Junshi, additional, Moore, Thomas B., additional, Mull, Ronald L., additional, Munro, Ian C., additional, Narahashi, Toshio, additional, Nishimura, Keiichiro, additional, Nitschke, Kenneth D., additional, Novak, Robert J., additional, O'Malley, Michael, additional, Oehme, Frederick W., additional, Ollinger, Janet, additional, Osimitz, Thomas G., additional, Pandian, Muhilan D., additional, Parsons, P.P., additional, Pelfrene, Alain F., additional, Pendino, Kimberly, additional, Petersen, Barbara J., additional, Pfeifer, Keith F., additional, Piccirillo, Vincent J., additional, Plimmer, Jack R., additional, Ponnock, Kathryn, additional, Pontal, Pierre-Gerard, additional, Pope, Carey, additional, Ray, David E., additional, Rieth, Joseph P., additional, Riviere, Jim E., additional, Rodgers, Kathleen E., additional, Romagni, Joanne G., additional, Ross, John H., additional, Rozman, Karl K., additional, Rubin, Carol H., additional, Rubin, Andrew L., additional, Rust, Michael K., additional, Ruzo, Luis O., additional, Sanderson, Wayne T., additional, Savolainen, Kai, additional, Schoenig, Gerald P., additional, Seiber, James N., additional, Sexton, Ken, additional, Sheets, Larry P., additional, Simpkins, James, additional, Slone, Thomas H., additional, Slovic, Paul, additional, Smith, Andrew G., additional, Snodgrass, Wayne R., additional, Solomon, Keith R., additional, Stevens, James T., additional, Stott, W.T., additional, Strong, Phillip L., additional, Gold, Lois Swirsky, additional, Takayama, Chiyozo, additional, Timchalk, Charles A., additional, Tobia, Abraham J., additional, Uchida, Matazaemon, additional, Ujváry, István, additional, van Hemmen, Joop J., additional, van Ravenswaay, Bennard, additional, Waechter, Felix, additional, Walls, Cassi L., additional, Weber, Edgar, additional, Wester, Ronald C., additional, Whitmyre, Gary K., additional, Wilks, Martin F., additional, Williams, Rick, additional, Wilson, Barry W., additional, Wilson, Alan G.E., additional, Yoshida, Masanori, additional, Youngren, Susan H., additional, and Zalom, Frank G., additional

Published
2001
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23. 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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27. A matter of life and death

Author

Hollingworth, Robert

Subjects
Death -- Evaluation, Life (Biology) -- Evaluation, History, Literature/writing
Abstract

An incident of a car accident on the side of a mountain near Tallarook by a woman that kills an Eastern Grey Kangaroo is described. As per Darwin 'life is just one great cone of variation with its tiny point in the dark annals of prehistory, that life started from a few witless blips in the past and expanded into the complexity we see today'.

Published
2004

41. The Safety of Genetically Modified Foods Produced through Biotechnology

Author

Hollingworth, Robert M., Bjeldanes, Leonard F., Bolger, Michael, Kimber, Ian, Meade, Barbara Jean, Taylor, Steve L., Wallace, Kendall B., Hollingworth, Robert M., Bjeldanes, Leonard F., Bolger, Michael, Kimber, Ian, Meade, Barbara Jean, Taylor, Steve L., and Wallace, Kendall B.

Abstract

The Society of Toxicology (SOT) is committed to protecting and enhancing human, animal, and environmental health through the sound application of the fundamental principles of the science of toxicology. It is with this goal in mind that the SOT defines here its current consensus position on the safety of foods produced through biotechnology (genetic engineering). These products are commonly termed genetically modified foods, but this is misleading, since conventional methods of microbial, crop, and animal improvement also produce genetic modifications and these are not addressed here. The available scientific evidence indicates that the potential adverse health effects arising from biotechnology-derived foods are not different in nature from those created by conventional breeding practices for plant, animal, or microbial enhancement, and are already familiar to toxicologists. It is therefore important to recognize that the food product itself, rather than the process through which it is made, should be the focus of attention in assessing safety. We support the use of the substantial equivalence concept as part of the safety assessment of biotechnology-derived foods. This process establishes whether the new plant or animal is significantly different from comparable, nonengineered plants or animals used to produce food that is generally considered to be safe for consumers. It provides critical guidance as to the nature of any increased health hazards in the new food. To establish substantial equivalence, extensive comparative studies of the chemical composition, nutritional quality, and levels of potentially toxic components, in both the engineered and conventional crop and animal, are conducted. Notable differences between the existing and new organism would require further evaluation to determine whether the engineered form presents a higher level of risk. Through this approach, the safety of current biotechnology-derived foods can be compared with that of their con

Published
2003

49. Preface

Author

HEDIN, PAUL A., primary, HOLLINGWORTH, ROBERT M., additional, MASLER, EDWARD P., additional, MIYAMOTO, JUNSHI, additional, and THOMPSON, DEAN G., additional

Published
1997
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