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)
Article
Cell Biology
Melanie Rall-Scharpf, Thomas W. P. Friedl, Shahar Biechonski, Michael Denkinger, Michael Milyavsky, Lisa Wiesmueller
Summary: The gender gap in DNA repair and its changes with aging have distinct effects on men and women.
Review
Genetics & Heredity
Leonhard Andreas Karl, Martina Peritore, Lorenzo Galanti, Boris Pfander
Summary: DNA double strand breaks (DSBs) are repaired in eukaryotes by various cellular mechanisms. Nucleosome remodelers, which have the ability to slide, evict, position, or edit nucleosomes, have emerged as key regulators of DSB repair. The activities of nucleosome remodelers at DSBs have been found to impact the decision-making process of DSB repair.
FRONTIERS IN GENETICS
(2022)
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.
Article
Cell Biology
Juliette Dabin, Margherita Mori, Sophie E. Polo
Summary: This review summarizes recent advances in understanding the coordination between chromatin maintenance and the DNA damage response (DDR) in the cell nucleus. The authors discuss how the DDR affects chromatin marks, organization, and mobility, and how chromatin alterations contribute to the DDR. They also present current knowledge of the molecular mechanisms underlying these processes in physiological and pathological conditions, and highlight unanswered questions in this field.
CURRENT OPINION IN CELL BIOLOGY
(2023)
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
Biotechnology & Applied Microbiology
Xavier Tatin, Giovanna Muggiolu, Sylvie Sauvaigo, Jean Breton
Summary: DNA double-strand breaks (DSBs) are harmful lesions that require repair to maintain molecular and genomic integrity. Various methods, including indirect and direct techniques, are available to measure DSB repair capacity, each with advantages and limitations. There is currently no ideal method to quantify DSBR capacity.
MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH
(2021)
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.
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
Cell Biology
Maria Svetlova, Ljudmila Solovjeva, Andrey Kropotov, Andrey Nikiforov
Summary: In this study, the impact of NAD bioavailability on DNA double-strand break (DSB) repair capacity was investigated in human dermal fibroblasts exposed to ionizing radiation. The results showed that high doses of radiation did not decrease intracellular NAD levels significantly. Additionally, even when NAD levels were depleted, cells were still able to repair DSB induced by radiation, although the efficiency was reduced compared to cells with normal NAD levels.
Review
Cell Biology
Nour L. Mozaffari, Fabio Pagliarulo, Alessandro A. Sartori
Summary: Human CtIP plays a crucial role in DNA repair, contributing to both genome integrity maintenance and oncogenic chromosomal translocations. Additionally, CtIP is involved in transcriptional regulation, DNA damage checkpoint signaling, and replication fork protection pathways.
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY
(2021)
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
Genetics & Heredity
Alice Libri, Timea Marton, Ludovic Deriano
Summary: DNA double-strand breaks are highly toxic and can be repaired via multiple DNA repair pathways. During V(D)J recombination, certain parameters restrict the repair of DSBs to the non-homologous end-joining pathway.
FRONTIERS IN GENETICS
(2022)
Article
Biology
Nadia Vertti-Quintero, Ethan Levien, Lucie Poggi, Ariel Amir, Guy-Franck Richard, Charles N. N. Baroud
Summary: This study demonstrates the use of microfluidic device to study DSBR at a single-cell level in yeast. The dynamics of DSBR were analyzed and a differential equation model was developed to obtain repair process rates. The study identified three types of DSB repair events that were previously unrecognized.
Review
Biochemistry & Molecular Biology
Ye -Rim Lee, Gi-Sue Kang, Taerim Oh, Hye-Ju Jo, Hye-Joon Park, G. -One Ahn
Summary: DNA-PKcs is a critical player in repairing DNA double-strand breaks and is involved in T and B cell development. Recent evidence suggests that DNA-PKcs not only functions in the nucleus but also in the cytoplasm, phosphorylating various proteins involved in cellular metabolism and cytokine production. Careful selection of experimental models is necessary when studying DNA-PKcs, as differences have been observed between cells with defective DNA-PKcs and cells with DNA-PKcs knockout. Additionally, the multiple functions and subcellular localization of DNA-PKcs in different cell types may complicate the effects of DNA-PK inhibitors in clinical trials.
MOLECULES AND CELLS
(2023)
Article
Cardiac & Cardiovascular Systems
Marta Perez-Hernandez, Alejandra Leo-Macias, Sarah Keegan, Mariam Jouni, Joon-Chul Kim, Esperanza Agullo-Pascual, Sarah Vermij, Mingliang Zhang, Feng-Xia Liang, Paul Burridge, David Fenyo, Eli Rothenberg, Mario Delmar
Summary: This study identified a subcellular domain formed by sodium channel clusters and subjacent subsarcolemmal mitochondria in adult cardiac myocytes, shedding light on the intersection between electrical and structural functions of the heart. The proximity of Na(V)1.5 channels to mitochondria resulted in functional changes in mitochondria upon TTX exposure, with increased Ca2+ accumulation and reactive oxygen species production. Additionally, a negative correlation between SCN5A and SLC8B1 at a transcriptional level was observed, highlighting the intricate crosstalk between sodium channels and mitochondria.
CIRCULATION RESEARCH
(2021)
Article
Genetics & Heredity
Carel Fijen, Eli Rothenberg
Summary: The formation of biomolecular condensates is crucial for cells to deal with stress and optimize enzymatic reactions, with RNA molecules and RNA-binding proteins playing important roles in double-strand break repair. The properties of condensates can influence the choice of repair pathway, and there are still open questions in this emerging field of research.
Article
Biochemistry & Molecular Biology
Ke Cong, Min Peng, Arne Nedergaard Kousholt, Wei Ting C. Lee, Silviana Lee, Sumeet Nayak, John Krais, Pamela S. VanderVere-Carozza, Katherine S. Pawelczak, Jennifer Calvo, Nicholas J. Panzarino, John J. Turchi, Neil Johnson, Jos Jonkers, Eli Rothenberg, Sharon B. Cantor
Summary: Mutations in BRCA1 or BRCA2 are found to be synthetic lethal with PARPi, with toxicity deriving from replication gaps instead of DNA double-stranded breaks. The study uncouples HR, FP, and fork speed from PARPi response, highlighting gaps as a determinant of PARPi toxicity and changing the paradigm for synthetic lethal interactions.
Article
Biochemistry & Molecular Biology
Yandong Yin, Wei Ting, Chelsea Lee, Dipika Gupta, Tony T. Huang, Mauro Modesti, Eli Rothenberg, Yandong Yin, Wei Ting Chelsea Lee
Summary: A study conducted using advanced microscopy techniques discovered that ATR plays a crucial role in monitoring and regulating the amounts of RPA at forks during unperturbed replication and replication stress. Replication stress amplifies the basal activity of ATR by increasing the ATR-RPA interaction and enrichment of ATR at specific sites, ultimately enhancing its activation and replication stress response.
Article
Cardiac & Cardiovascular Systems
Jingjing Zheng, Holly C. Dooge, Marta Perez-Hernandez, Yan-Ting Zhao, Xi Chen, Jonathan J. Hernandez, Carmen R. Valdivia, Julieta Palomeque, Eli Rothenberg, Mario Delmar, Hector H. Valdivia, Francisco J. Alvarado
Summary: RyR2 is a crucial protein in the heart that regulates the release of Ca2+. This study found that a decrease in RyR2 expression has limited impact on overall cardiac function, highlighting the redundancy of RyR2 protein expression and the plasticity of the excitation-contraction coupling apparatus.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
(2022)
Article
Multidisciplinary Sciences
Kate E. Coleman, Yandong Yin, Sarah Kit Leng Lui, Sarah Keegan, David Fenyo, Duncan J. Smith, Eli Rothenberg, Tony T. Huang
Summary: This study provides mechanistic insights into how auto-cleavage of the USP1 deubiquitinase regulates DNA replication and genome stability, and discusses the implications for cancer therapy by targeting USP1 activity via protein-DNA trapping.
NATURE COMMUNICATIONS
(2022)
Review
Cell Biology
Shaun M. Christie, Carel Fijen, Eli Rothenberg
Summary: V(D)J recombination is a crucial mechanism in the adaptive immune system, generating diverse antigen receptors. This review focuses on the regulatory functions of RAGs, recruitment of RAGs and formation of paired complexes, transition from post-cleavage complex to repair phase, and redundant roles of certain factors in break repair. Understanding these processes is important for avoiding off-target recombination or deficiency-mediated clinical manifestations.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Cardiac & Cardiovascular Systems
Marta Perez-Hernandez, Chantal J. M. van Opbergen, Navratan Bagwan, Christoffer Rasmus Vissing, Grecia M. Marron-Linares, Mingliang Zhang, Estefania Torres Vega, Andrea Sorrentino, Lylia Drici, Karolina Sulek, Ruxu Zhai, Finn B. Hansen, Alex Horby Christensen, Soren Boesgaard, Finn Gustafsson, Kasper Rossing, Eric M. Small, Michael J. Davies, Eli Rothenberg, Priscila Y. Sato, Marina Cerrone, Thomas Hartvig Lindkaer Jensen, Klaus Qvortrup, Henning Bundgaard, Mario Delmar, Alicia Lundby
Summary: This study provides a comprehensive characterization of the molecular landscape of ARVC, revealing the key role of nuclear envelope integrity loss and subsequent DNA damage in the disease. The findings suggest that therapies targeting oxidant formation may be a potential intervention to restrict DNA damage in ARVC.
Article
Biology
Judit Jimenez-Sainz, Joshua Mathew, Gemma Moore, Sudipta Lahiri, Jennifer Garbarino, Joseph P. Eder, Eli Rothenberg, Ryan B. Jensen
Summary: This study identified three BRCA2 VUS located in the BRC repeat region and investigated their impact on genome stability. The S1221P and T1980I mutations were found to compromise the cellular response to chemotherapeutics and ionizing radiation, and showed deficits in fork protection. The T1346I mutation, on the other hand, was fully functional. The correct classification of BRCA2 VUS is important as pathogenic variants can impact cancer risk and guide therapy selection during cancer treatment.
Article
Multidisciplinary Sciences
Huijun Xue, Amit Bhardwaj, Yandong Yin, Carel Fijen, Anastasiya Ephstein, Lianglin Zhang, Xia Ding, John M. Pascal, Todd L. VanArsdale, Eli Rothenberg
Summary: PARP inhibitors modulate the retention of PARP1 on DNA lesions through a two-step mechanism, involving competitive inhibition of NAD(+) binding and allosteric modulation. The retention potency of PARPi is predominantly determined by its ability to outcompete NAD(+) binding.
Article
Multidisciplinary Sciences
Sameera Vipat, Dipika Gupta, Sagun Jonchhe, Hele Anderspuk, Eli Rothenberg, Tatiana N. Moiseeva
Summary: DNA polymerase epsilon plays a critical role in DNA replication initiation. In human cancer cells, POLE is dispensable for replicative helicase assembly but essential for replication initiation, requiring the non-catalytic domain of POLE1.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Shaun M. Christie, Takuya Tada, Yandong Yin, Amit Bhardwaj, Nathaniel R. Landau, Eli Rothenberg
Summary: This article examines the interaction between SARS-CoV-2 variants and target cells, revealing a progressive decrease in dependence on ACE2. These findings are crucial for vaccine development.
Article
Biochemistry & Molecular Biology
Antonia Kefala Stavridi, Amandine Gontier, Vincent Morin, Philippe Frit, Virginie Ropars, Nadia Barboule, Carine Racca, Sagun Jonchhe, Michael J. Morten, Jessica Andreani, Alexey Rak, Pierre Legrand, Alexa Bourand-Plantefol, Steven W. Hardwick, Dimitri Y. Chirgadze, Paul Davey, Taiana Maia De Oliveira, Eli Rothenberg, Sebastien Britton, Patrick Calsou, Tom L. Blundell, Paloma F. Varela, Amanda K. Chaplin, Jean-Baptiste Charbonnier
Summary: This study reveals the molecular mechanism by which the interaction between the Ku70-Ku80 heterodimer and inositol-hexaphosphate (IP6) enhances the activity of classical Non-Homologous End Joining (c-NHEJ) pathway for DNA repair.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Multidisciplinary Sciences
Aina Maria Mas, Enrique Goni, Igor Ruiz de los Mozos, Aida Arcas, Luisa Statello, Jovanna Gonzalez, Lorea Blazquez, Wei Ting Chelsea Lee, Dipika Gupta, Alvaro Sejas, Shoko Hoshina, Alexandros Armaos, Gian Gaetano Tartaglia, Shou Waga, Jernej Ule, Eli Rothenberg, Maria Gomez, Maite Huarte
Summary: In this study, the authors demonstrate that ORC1, a subunit of the Origin Recognition Complex, interacts with RNAs transcribed from genes with origins of replication at their TSSs, and this interaction positively correlates with origin activation. They show that the binding of RNA to ORC1 facilitates chromatin release and activation of proximal origins, and this process is regulated by phosphorylation and degradation. These findings reveal a novel non-coding function of RNA in coordinating the activation of replication origins.
NATURE COMMUNICATIONS
(2023)
Article
Oncology
Jiehui Deng, Aatish Thennavan, Igor Dolgalev, Ting Chen, Jie Li, Antonio Marzio, John T. Poirier, David H. Peng, Mirna Bulatovic, Subhadip Mukhopadhyay, Heather Silver, Eleni Papadopoulos, Val Pyon, Cassandra Thakurdin, Han Han, Fei Li, Shuai Li, Hailin Ding, Hai Hu, Yuanwang Pan, Vajira Weerasekara, Baishan Jiang, Eric S. Wang, Ian Ahearn, Mark Philips, Thales Papagiannakopoulos, Aristotelis Tsirigos, Eli Rothenberg, Justin Gainor, Gordon J. Freeman, Charles M. Rudin, Nathanael S. Gray, Peter S. Hammerman, Michele Pagano, John V. Heymach, Charles M. Perou, Nabeel Bardeesy, Kwok-Kin Wong
Summary: The study found that LKB1-deficient lung tumors are sensitive to autophagy inhibition, which can restore impaired antigen presentation and antitumor immune responses, enhancing the effectiveness of PD-1 immunotherapy. Additionally, LKB1 deficiency inhibits antigen processing and presentation, but this can be reversed by targeting the autophagy pathway to restore immunoproteasome activity and antigen presentation.
