Review
Biochemistry & Molecular Biology
Jessica Kelliher, Gargi Ghosal, Justin Wai Chung Leung
Summary: The chromatin-based DNA damage response pathway is regulated by histone post-translational modifications, including histone H2A ubiquitination. RNF168 plays a crucial role in assembling DNA repair proteins at damaged chromatin through its enzymatic activity. Understanding the specificity of RNF168 targeting could have implications for cancer treatment.
Article
Biochemistry & Molecular Biology
Ioannis Emmanouilidis, Natalia Fili, Alexander W. Cook, Yukti Hari-Gupta, Alia dos Santos, Lin Wang, Marisa L. Martin-Fernandez, Peter J. I. Ellis, Christopher P. Toseland
Summary: Mammalian cells are constantly exposed to various DNA damaging events, leading to the activation of DNA repair pathways. Cas9-based genomic intervention allows for induced DSBs at defined quantities and locations across the human genome, utilizing custom-designed promiscuous guide RNAs based on in silico predictions. This provides a generic, low-cost, and rapid methodology for inducing controlled DNA damage in cell culture models.
Review
Biochemistry & Molecular Biology
Vincent E. Provasek, Joy Mitra, Vikas H. Malojirao, Muralidhar L. Hegde
Summary: The continuous process of DNA damage and repair is crucial for maintaining genomic integrity. Among different types of DNA damage, double-strand breaks (DSBs) are the most dangerous and require timely repair. DSB repair is particularly important for nondividing, post-mitotic cells in the central nervous system (CNS), as failure in these mechanisms can lead to disruptions in neural networks and motor functions. In addition to repair pathways, DNA damage response (DDR) signaling and hnRNP proteins have been found to play important roles in neuronal DSB repair and are linked to age-associated neurological disorders.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Geriatrics & Gerontology
Evrydiki Kravvariti, Panagiotis A. Ntouros, Nikolaos Vlachogiannis, Maria Pappa, Vassilis L. Souliotis, Petros P. Sfikakis
Summary: Defects in the DNA damage response and repair network accumulate during aging, leading to physical frailty. This study found that older individuals had increased levels of oxidative stress and DNA damage, as well as reduced DNA repair capacity, compared to younger controls. These abnormalities were more pronounced in frail older adults and were associated with individual frailty levels, suggesting their potential as biomarkers for frailty.
JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES
(2023)
Review
Cell Biology
Devon M. Fitzgerald, Susan M. Rosenberg
Summary: The Escherichia coli SOS response to DNA damage, discovered by Evelyn Witkin and Miroslav Radman, is the prototypic DNA-damage stress response that upregulates proteins for protection and repair. Similar mechanisms are found across species and contribute to genome instability in human cancer and aging. Bacterial molecular genomic mechanisms can offer insights into universal biology, including in human disease.
Article
Cell Biology
Jong-Hyuk Lee, Raghavendra A. Shamanna, Tomasz Kulikowicz, Nima Borhan Fakouri, Edward W. Kim, Louise S. Christiansen, Deborah L. Croteau, Vilhelm A. Bohr
Summary: Werner syndrome (WS) is an accelerated aging disorder characterized by genomic instability caused by WRN protein deficiency. The phosphorylation of WRN by CDK2 on serine residue 426 is critical for WRN to choose between non-homologous end joining (NHEJ) and homologous recombination (HR) pathways. The phosphorylation stabilizes WRN's affinity for RPA and enhances its role in long-range resection, a crucial step for HR.
Review
Genetics & Heredity
Gerarda van de Kamp, Tim Heemskerk, Roland Kanaar, Jeroen Essers
Summary: Particle radiation, with its superior dose distribution compared to photon radiation, shows promise for tumor treatment. However, the cellular responses, particularly the DNA damage response (DDR), to particle therapy are not well characterized. Current investigations are focused on how the spatial configuration of DNA damage induced by particles influences DNA repair pathway usage.
FRONTIERS IN GENETICS
(2021)
Review
Cell Biology
Ksenia G. Kolobynina, Alexander Rapp, M. Cristina Cardoso
Summary: Chromatin serves as the background for all DNA-based molecular processes in the cell nucleus. The initial chromatin structure at the site of DNA damage determines lesion generation and activation of the DNA damage response pathway. Ubiquitination, as an important chromatin post-translational modification, is involved in chromatin changes at the damaged site and throughout the genome.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Julie A. Klaric, Stas Wust, Stephanie Panier
Summary: DNA double-strand breaks are cytotoxic DNA lesions that trigger a complex signaling response in cells to protect genomic stability. RNA-binding proteins play a crucial role in this response, with functions extending beyond gene expression to participate in DNA repair and signal transduction processes at damaged chromatin. Their involvement in the DSB response also has implications for genome instability and age-related diseases like cancer and neurodegeneration.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Article
Cell Biology
Arthur Aubry, Joel D. Pearson, Jason Charish, Tao Yu, Jeremy M. Sivak, Dimitris P. Xirodimas, Herve Avet-Loiseau, Jill Corre, Philippe P. Monnier, Rod Bremner
Summary: The neddylation inhibitor MLN4924/Pevonedistat is under clinical trials for various types of cancers. It shows efficacy by inhibiting multiple cellular networks and synergizing with standard-of-care drugs, potentially providing a broad therapeutic relevance.
Review
Cell Biology
Huiming Lu, Anthony J. Davis
Summary: RecQ DNA helicases are a conserved protein family found in various organisms, playing important roles in cellular functions and potentially contributing to autosomal disorders.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Genetics & Heredity
Fabiola Garcia Fernandez, Emmanuelle Fabre
Summary: Research has shown that chromatin mobility is affected by DNA damage. In the case of double-strand breaks, the mobility of chromatin at the break site is severely affected, while that of other chromosomes is affected to a lesser extent.
Article
Multidisciplinary Sciences
Ali Abu Shqair, Ui-Seob Lee, Eun-Hee Kim
Summary: In cellular experiments, a practical modelling has been developed to simulate the occurrences of double-strand breaks (DSBs) and the formations of gamma-H2AX foci in response to individual DSB formations, in cell nucleus due to exposure to alpha particles. This computational modelling can better implement the conventional gamma-H2AX assay.
SCIENTIFIC REPORTS
(2022)
Article
Cell Biology
You-hong Wang, Zhen Guo, Liang An, Yong Zhou, Heng Xu, Jing Xiong, Zhao-qian Liu, Xiao-ping Chen, Hong-hao Zhou, Xiong Li, Tao Liu, Wei-hua Huang, Wei Zhang
Summary: This study found that LINC-PINT is significantly downregulated in nasopharyngeal cancer tissues compared to rhinitis tissues, and low LINC-PINT expressions are associated with poorer prognosis in patients receiving radiotherapy. LINC-PINT plays a functional role in inhibiting malignant phenotypes and sensitizing cancer cells to irradiation in vitro and in vivo. Mechanistically, LINC-PINT inhibits DNA damage repair through the ATM/ATR-Chk1/Chk2 signaling pathways and increases radiosensitivity by interacting with DNA-PKcs.
CELL DEATH & DISEASE
(2021)
Article
Oncology
Jiali Qin, Jie Fan, Gang Li, Shanting Liu, Zhensheng Liu, Yao Wu
Summary: The study found that radiation exposure may lead to mutations in DNA double-strand break repair genes, resulting in decreased DSB repair capacity and increased risk of PTMC.
CANCER CELL INTERNATIONAL
(2021)
Article
Multidisciplinary Sciences
Rimma Belotserkovskaya, Elisenda Raga Gil, Nicola Lawrence, Richard Butler, Gillian Clifford, Marcus D. Wilson, Stephen P. Jackson
NATURE COMMUNICATIONS
(2020)
Article
Multidisciplinary Sciences
Donna J. Lowe, Mareike Herzog, Thorsten Mosler, Howard Cohen, Sarah Felton, Petra Beli, Ken Raj, Yaron Galanty, Stephen P. Jackson
SCIENTIFIC REPORTS
(2020)
Article
Biology
Anne Ramsay Bowden, David A. Morales-Juarez, Matylda Sczaniecka-Clif, Maria Martin Agudo, Natalia Lukashchuk, John Christopher Thomas, Stephen P. Jackson
Retraction
Multidisciplinary Sciences
Chanchal Sow, Shingo Yonezawa, Sota Kitamura, Takashi Oka, Kazuhiko Kuroki, Fumihiko Nakamura, Yoshiteru Maeno
Article
Biochemistry & Molecular Biology
Takashi Ochi, Valentina Quarantotti, Huawen Lin, Jerome Jullien, Ivan Rosa e Silva, Francesco Boselli, Deepak D. Barnabas, Christopher M. Johnson, Stephen H. McLaughlin, Stefan M. Freund, Andrew N. Blackford, Yuu Kimata, Raymond E. Goldstein, Stephen P. Jackson, Tom L. Blundell, Susan K. Dutcher, Fanni Gergely, Mark van Breugel
Article
Urology & Nephrology
Marine Berquez, Jonathan R. Gadsby, Beatrice Paola Festa, Richard Butler, Stephen P. Jackson, Valeria Berno, Alessandro Luciani, Olivier Devuyst, Jennifer L. Gallop
KIDNEY INTERNATIONAL
(2020)
Correction
Genetics & Heredity
Anton G. Henssen, Richard Koche, Jiali Zhuang, Eileen Jiang, Casie Reed, Amy Eisenberg, Eric Still, Ian C. MacArthur, Elias Rodriguez-Fos, Santiago Gonzalez, Montserrat Puiggros, Andrew N. Blackford, Christopher E. Mason, Elisa de Stanchina, Mithat Gonen, Anne-Katrin Emde, Minita Shah, Kanika Arora, Catherine Reeves, Nicholas D. Socci, Elizabeth Perlman, Cristina R. Antonescu, Charles W. M. Roberts, Hanno Steen, Elizabeth Mullen, Stephen P. Jackson, David Torrents, Zhiping Weng, Scott A. Armstrong, Alex Kentsis
Article
Multidisciplinary Sciences
Nicola A. Thompson, Marco Ranzani, Louise van der Weyden, Vivek Iyer, Victoria Offord, Alastair Droop, Fiona Behan, Emanuel Goncalves, Anneliese Speak, Francesco Iorio, James Hewinson, Victoria Harle, Holly Robertson, Elizabeth Anderson, Beiyuan Fu, Fengtang Yang, Guido Zagnoli-Vieira, Phil Chapman, Martin Del Castillo Velasco-Herrera, Mathew J. Garnett, Stephen P. Jackson, David J. Adams
Summary: Genetic redundancy plays a crucial role in cell survival and tumor adaptation. The study reveals the impact of FAM50A/FAM50B paralogues on cellular fitness across multiple cell lines, shedding new light on the fitness effects of cancer cells.
NATURE COMMUNICATIONS
(2021)
Review
Cell Biology
Domenic Pilger, Leonard W. Seymour, Stephen P. Jackson
Summary: The DNA damage response (DDR) is essential for preserving genome integrity, with targeting DDR in tumors showing remarkable success in cancer therapy. Recent studies suggest that DDR inhibitors impact cellular immune responses, and efforts have been made to develop immune checkpoint inhibitors to overcome immune suppression in tumors. Combining DDR inhibitors with immune checkpoint antagonists may offer new therapeutic strategies, although there are current limitations to broader therapeutic applications.
GENES & DEVELOPMENT
(2021)
Article
Biochemistry & Molecular Biology
Mareike Herzog, Elisa Alonso-Perez, Israel Salguero, Jonas Warringer, David J. Adams, Stephen P. Jackson, Fabio Puddu
Summary: The study shows that yeast cells carrying a range of cancer-associated mutations in the Pol ε exonuclease domain exhibit ultra-mutagenesis, with similarities to mutations observed in cells lacking the exonuclease domain. This suggests a shared mechanism of mutagenesis leading to mutation patterns similar to cancer Signature 14.
NUCLEIC ACIDS RESEARCH
(2021)
Editorial Material
Cell Biology
Christopher J. Carnie, Stephen P. Jackson
Summary: Transcription-coupled repair of DNA lesions occurs in all domains of life, with a highly conserved transcription-elongation factor ELOF1 playing a key role in the process in eukaryotes. Additionally, evidence of a second transcription-coupled repair pathway has been found in mammalian cells.
NATURE CELL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Rebecca L. Lloyd, Vaclav Urban, Francisco Munoz-Martinez, Inigo Ayestaran, John C. Thomas, Christelle de Renty, Mark J. O'Connor, Josep Forment, Yaron Galanty, Stephen P. Jackson
Summary: The protein kinase ATR is crucial for DNA repair and cell cycle regulation, with ATR inhibitors being developed for cancer treatment. The study identifies Cyclin C and CDK8 as resistance genes to ATR inhibitors, and highlights transcription-associated replication stress as a major driver of ATRi-induced cell death.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Maria Jose Cabello-Lobato, Matthew Jenner, Metztli Cisneros-Aguirre, Kira Bruninghoff, Zac Sandy, Isabelle C. da Costa, Thomas A. Jowitt, Christian M. Loch, Stephen P. Jackson, Qian Wu, Henning D. Mootz, Jeremy M. Stark, Matthew J. Cliff, Christine K. Schmidt
Summary: SUMOylation plays a critical role in maintaining genome integrity through the repair of DNA double-strand breaks (DSBs). This study identifies two non-conventional SUMO2-binding regions on XRCC4, a DNA repair protein involved in non-homologous end-joining (NHEJ) DSB repair. Results suggest that SUMO2 forms a redundant layer in NHEJ that regulates multiple NHEJ complexes, including XRCC4 interactions with other important proteins.
NUCLEIC ACIDS RESEARCH
(2022)
Review
Cell Biology
Samah W. W. Awwad, Almudena Serrano-Benitez, John C. C. Thomas, Vipul Gupta, Stephen P. P. Jackson
Summary: This review discusses the mechanistic basis of CRISPR-Cas genetic screening approaches and describes how they have contributed to our understanding of DNA repair and DDR pathways. It also highlights the impacts of CRISPR-based studies in identifying novel strategies for cancer therapy and in understanding, overcoming, and even exploiting cancer-drug resistance.
NATURE REVIEWS MOLECULAR CELL BIOLOGY
(2023)
Article
Oncology
David A. Morales-Juarez, Stephen P. Jackson
Summary: The discovery of synthetic lethal interactions between genetic deficiencies and cancers has identified potential targets for drug development, although their clinical success varies. Research has found a promising synthetic lethal interaction between inactivation/inhibition of the WRN DNA helicase and tumors with microsatellite instability, which arises from DNA mismatch repair deficiency. However, suitable compounds for clinical use have yet to be described. The complexities of microsatellite instability development and its relation to cancer evolution pose challenges for clinical prospects.
NPJ PRECISION ONCOLOGY
(2022)
