Article
Biology
Wisoo Shin, Whitney Alpaugh, Laura J. Hallihan, Sarthak Sinha, Emilie Crowther, Gary R. Martin, Teresa Scheidl-Yee, Xiaoyan Yang, Grace Yoon, Taylor Goldsmith, Nelson D. Berger, Luiz G. N. de Almeida, Antoine Dufour, Ina Dobrinski, Michael Weinfeld, Frank R. Jirik, Jeff Biernaskie
Summary: DNA repair protein PNKP is crucial for maintaining genomic integrity, and its global disruption in adult mice results in a premature aging-like phenotype with impaired growth of hair follicles, seminiferous tubules, and neural progenitor cell populations, highlighting its important role in normal growth and survival of these murine progenitor populations.
LIFE SCIENCE ALLIANCE
(2021)
Article
Biochemistry & Molecular Biology
Sonja Neuser, Ilona Krey, Annemarie Schwan, Rami Abou Jamra, Tobias Bartolomaeus, Jan Doering, Steffen Syrbe, Margit Plassmann, Stefan Rohde, Christian Roth, Helga Rehder, Maximilian Radtke, Diana Le Duc, Susanna Schubert, Luis Bermudez-Guzman, Alejandro Leal, Katharina Schoner, Bernt Popp
Summary: This study presents the first prenatal diagnosis of PNKP-related primary microcephaly and characterizes the effects of PNKP variants through RNA analysis and structural modeling. Retrospective investigation of two individuals with biallelic PNKP variants reveals complex splicing patterns and highlights the potential structural damage caused by missense variants in the FHA domain. These findings extend the clinical spectrum of PNKP-related disorders to the prenatal stage and provide insights into a framework for PNKP variant characterization.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2022)
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
Matvey Mikhailovich Murashko, Ekaterina Mikhailovna Stasevich, Anton Markovich Schwartz, Dmitriy Vladimirovich Kuprash, Aksinya Nicolaevna Uvarova, Denis Eriksonovich Demin
Summary: Incorrect repair of DNA double-strand breaks leading to chromosomal rearrangements is a major cause of oncogenesis. Recent studies have highlighted the key role of various types of RNA in the formation, recognition, and repair of DSBs, with gene mutations or changes in RNA expression levels potentially leading to DNA repair defects and increased chromosome aberration frequency. Additionally, certain RNAs have been shown to stimulate long-range chromosomal rearrangements, and further research is needed to understand how RNA mediates specific chromosomal rearrangements.
Review
Neurosciences
Charles K. Davis, Raghu Vemuganti
Summary: The study explores the mechanisms of DNA damage and repair induced by TBI, and discusses potential experimental therapies targeting DNA repair process members for improved outcomes following TBI.
NEUROBIOLOGY OF DISEASE
(2021)
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
Biochemistry & Molecular Biology
Almudena Serrano-Benitez, Sophie E. Wells, Lylah Drummond-Clarke, Lilian C. Russo, John Christopher Thomas, Giovanna A. Leal, Mark Farrow, James Michael Edgerton, Shankar Balasubramanian, Ming Yang, Christian Frezza, Amit Gautam, Jan Brazina, Kamila Burdova, Nicolas C. Hoch, Stephen P. Jackson, Keith W. Caldecott
Summary: DNA single-strand breaks (SSBs) play a role in disrupting DNA replication and causing chromosome breakage. This study investigates whether SSBs induce chromosome breakage when located behind or ahead of replication forks, and finds that only SSBs ahead of replication forks trigger fork collapse and chromosome breakage. Furthermore, the study shows that CldU, a thymidine analogue, is cytotoxic to cells lacking SSB repair mechanisms and its incorporation in template DNA is particularly harmful during the following cell cycle. Additionally, BRCA-defective cells are highly sensitive to CldU, suggesting its potential clinical utility.
Article
Genetics & Heredity
Ann-Charlotte Thuresson, Jan Brazina, Talia Akram, Julia Albrecht, Niklas Dahl, Cecilia Soussi Zander, Keith W. Caldecott
Summary: This study identified compound heterozygous variants in the PNKP gene associated with MCSZ. Experimental results showed that these variants led to reduced levels of PNKP protein, which affected the repair of DNA single-strand breaks.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2023)
Editorial Material
Biotechnology & Applied Microbiology
Megumi Ishii, Tetsuya Ishii
Summary: This passage discusses whether genome-edited agricultural products should be considered genetically modified organisms (GMOs) and how to prove definitively that a genome-edited organism does not contain exogenous DNA, taking social aspects into account.
TRENDS IN BIOTECHNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Sahar Waseem, Sudeep Kumar, Kanghoon Lee, Byoung-Ha Yoon, Mirang Kim, Hail Kim, Keesook Lee
Summary: PRMT1 is crucial for male fertility in mice, as its deficiency leads to impaired repair pathway of DNA double-strand breaks in male germ cells. This study provides new insight into the role of PRMT1-mediated asymmetric demethylation in mouse spermatogenesis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Eva L. Morozko, Charlene Smith-Geater, Alejandro Mas Monteys, Subrata Pradhan, Ryan G. Lim, Peter Langfelder, Marketta Kachemov, Austin Hill, Jennifer T. Stocksdale, Pieter R. Cullis, Jie Wu, Joseph Ochaba, Ricardo Miramontes, Anirban Chakraborty, Tapas K. Hazra, Alice Lau, Sophie St-Cyr, Iliana Orellana, Lexi Kopan, Keona Q. Wang, Sylvia Yeung, Blair R. Leavitt, Jack C. Reidling, X. William Yang, Joan S. Steffan, Beverly L. Davidson, Partha S. Sarkar, Leslie M. Thompson
Summary: This study reveals the involvement of PIAS1 in DNA damage repair pathways and its connection with transcriptional modulation in neurodegenerative diseases. Knockdown of PIAS1 in HD mice normalizes transcriptional dysregulation and DNA damage repair mechanisms, impacting genomic integrity in neurons. The findings highlight the role of SUMO modifying machinery in DNA damage repair responses and transcriptional modulation in the context of neurodegenerative disease.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Shan Huang, Kaihang Wang, Stephen L. Mayo
Summary: A recent study shows that CbAgo, a prokaryotic argonaute, can induce DNA interference and generate double-stranded breaks in target DNAs. The study demonstrates that CbAgo can cleave genome target sites and induce chromosome recombination in Escherichia coli. The findings suggest that the guide-directed cleavage of pAgo on the host genome is mutagenic and can be utilized in genetic manipulation.
NUCLEIC ACIDS RESEARCH
(2023)
Review
Genetics & Heredity
Judith Mine-Hattab, Siyu Liu, Angela Taddei
Summary: This article discusses the physical nature of DNA repair foci, including liquid-liquid phase separation and its role in the formation and disassembly of foci. The article introduces different models of condensates and discusses evidence of liquid phase separation at DNA repair sites, and finally explores the origin and possible function of liquid phase separation in DNA repair processes.
Article
Biochemistry & Molecular Biology
Upasana Roy, Youngho Kwon, Lea Marie, Lorraine Symington, Patrick Sung, Michael Lisby, Eric C. Greene
Summary: The study reveals that Rad55-Rad57 promotes rapid re-assembly of Rad51 filaments after disruption by Srs2, supporting a model in which Rad51 is in flux between free and single-stranded DNA-bound states.
Article
Multidisciplinary Sciences
Jakub Wiktor, Arvid H. Gynna, Prune Leroy, Jimmy Larsson, Giovanna Coceano, Ilaria Testa, Johan Elf
Summary: Homologous recombination is crucial for accurate DNA repair, with repair of double-stranded DNA breaks in E. coli completed in approximately 15 minutes. The search for homologous repair templates takes less than 9 minutes and is mediated by a thin and highly dynamic RecA filament stretching throughout the cell. This model effectively reduces search dimensionality, with search time consistent across different cell lengths and DNA amounts.
Article
Biochemistry & Molecular Biology
Emilia Komulainen, Jack Badman, Stephanie Rey, Stuart Rulten, Limei Ju, Kate Fennell, Ilona Kalasova, Kristyna Ilievova, Peter J. McKinnon, Hana Hanzlikova, Kevin Staras, Keith W. Caldecott
Summary: The study demonstrates that high activity of DNA strand break sensor protein Parp1 in mice with Xrcc1 deletion can result in lethal seizures, which can be prevented and lifespan extended by inhibiting or deleting Parp1. This highlights PARP inhibition as a potential therapeutic approach for hereditary neurological diseases.
Article
Multidisciplinary Sciences
Wei Wu, Sarah E. Hill, William J. Nathan, Jacob Paiano, Elsa Callen, Dongpeng Wang, Kenta Shinoda, Niek van Wietmarschen, Jennifer M. Colon-Mercado, Dali Zong, Raffaella De Pace, Han-Yu Shih, Steve Coon, Maia Parsadanian, Raphael Pavani, Hana Hanzlikova, Solji Park, Seol Kyoung Jung, Peter J. McHugh, Andres Canela, Chongyi Chen, Rafael Casellas, Keith W. Caldecott, Michael E. Ward, Andre Nussenzweig
Summary: Defects in DNA repair can lead to neurodevelopmental and neurodegenerative diseases, particularly in long-lived post-mitotic neurons. Neurons accumulate unexpectedly high levels of DNA single-strand breaks at specific sites within the genome, which are repaired by PARP1 and XRCC1-dependent mechanisms. Deficiencies in XRCC1-dependent repair in neurons can lead to increased DNA repair synthesis at neuronal enhancers, while defects in long-patch repair reduce synthesis, potentially contributing to neurodegenerative phenotypes in patients.
Article
Biochemistry & Molecular Biology
Annie A. Demin, Kouji Hirota, Masataka Tsuda, Marek Adamowicz, Richard Hailstone, Jan Brazina, William Gittens, Ilona Kalasova, Zhengping Shao, Shan Zha, Hiroyuki Sasanuma, Hana Hanzlikova, Shunichi Takeda, Keith W. Caldecott
Summary: PARPs and XRCC1 accelerate mammalian DNA base excision repair (BER), where XRCC1 prevents excessive PARP1 engagement during BER and traps PARP1 on BER intermediates. Excessive PARP1 engagement poses a threat to genome integrity, while XRCC1 acts as an anti-trapper preventing toxic PARP1 activity. Deletion of PARP1 rescues BER and resistance to base damage in XRCC1-deficient cells.
Article
Nutrition & Dietetics
Edward A. Ruiz-Narvaez, Ana Baylin, Jorge Azofeifa, Alejandro Leal, Luis Rosero-Bixby
Summary: This study aimed to identify dietary factors associated with leukocyte telomere length in the elderly population of Costa Rica. The results suggest that a traditional Costa Rican dietary pattern is positively associated with telomere length, potentially contributing to the extended longevity of elderly Costa Ricans.
Article
Biochemistry & Molecular Biology
Sonja Neuser, Ilona Krey, Annemarie Schwan, Rami Abou Jamra, Tobias Bartolomaeus, Jan Doering, Steffen Syrbe, Margit Plassmann, Stefan Rohde, Christian Roth, Helga Rehder, Maximilian Radtke, Diana Le Duc, Susanna Schubert, Luis Bermudez-Guzman, Alejandro Leal, Katharina Schoner, Bernt Popp
Summary: This study presents the first prenatal diagnosis of PNKP-related primary microcephaly and characterizes the effects of PNKP variants through RNA analysis and structural modeling. Retrospective investigation of two individuals with biallelic PNKP variants reveals complex splicing patterns and highlights the potential structural damage caused by missense variants in the FHA domain. These findings extend the clinical spectrum of PNKP-related disorders to the prenatal stage and provide insights into a framework for PNKP variant characterization.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2022)
Article
Genetics & Heredity
Keith W. Caldecott, Michael E. Ward, Andre Nussenzweig
Summary: The neuronal genome is highly sensitive to loss or impairment of DNA repair. Recent studies have revealed unexpected high levels of 'programmed' DNA breakage in neurons. These breaks are believed to occur during normal processes of neuronal development and maintenance. The role of programmed DNA breaks in neuronal physiology and disease remains relatively unexplored. However, sequencing analyses of neurodegenerative diseases have found age-related somatic mutational signatures enriched in regulatory regions of the genome.
Article
Biochemistry & Molecular Biology
Alina Vaitsiankova, Kamila Burdova, Margarita Sobol, Amit Gautam, Oldrich Benada, Hana Hanzlikova, Keith W. Caldecott
Summary: PARP inhibitors hinder the maturation of nascent DNA strands during DNA replication, particularly unligated Okazaki fragments and other discontinuities, resulting in cytotoxic effects. The activation of PARP1 is elevated in cells lacking the FEN1 nuclease, suggesting its involvement in the detection and processing of these DNA replication intermediates. PARP inhibitors disrupt the integrity of nascent DNA strands in both normal and FEN1(-/-) cells, leading to the formation of single-strand nicks or gaps. These findings highlight the importance of unligated Okazaki fragments and other discontinuities in the cytotoxicity of PARP inhibitors.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2022)
Review
Cell Biology
Keith W. Caldecott
Summary: DNA single-strand breaks (SSBs) are common DNA lesions in cells and can arise from exposure to genotoxins or normal DNA metabolic processes. If left unrepaired, SSBs can have serious consequences, including neurodegenerative diseases. This review discusses the current understanding of SSB repair mechanisms and their impact on neurological diseases.
TRENDS IN CELL BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Zuzana Cihlarova, Jan Kubovciak, Margarita Sobol, Katerina Krejcikova, Jana Sachova, Michal Kolar, David Stanek, Cyril Barinka, Grace Yoon, Keith W. Caldecott, Hana Hanzlikova
Summary: Mutations in BRAT1 are associated with neurodevelopmental delay and neurodegeneration. This study reveals that BRAT1 is a component of Integrator and plays a crucial role in the processing of specific RNAs. The authors also demonstrate that patient-derived cells with BRAT1 mutations show reduced levels of the Integrator catalytic subunit and impaired RNA processing.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Amit Gautam, Heather Fawcett, Kamila Burdova, Jan Brazina, Keith W. Caldecott
Summary: This study identified a DNA base excision repair process in normal human cells that can rapidly remove a subset of photodimers induced by UV irradiation. This repair process functions independently of nucleotide excision repair.