Article
Biochemistry & Molecular Biology
Katja Kratz, Mariela Artola-Boran, Saho Kobayashi-Era, Gene Koh, Goncalo Oliveira, Shunsuke Kobayashi, Andreia Oliveira, Xueqing Zou, Julia Richter, Masataka Tsuda, Hiroyuki Sasanuma, Shunichi Takeda, Joanna Loizou, Alessandro A. Sartori, Serena Nik-Zainal, Josef Jiricny
Summary: A study revealed a new exonuclease, FAN1, which can efficiently substitute for EXO1 in the mismatch repair process, with its functional complementation modulated by its interaction with MLH1. Loss of FAN1 exacerbates the mutational profile of EXO1-deficient cells, suggesting redundant action of these two nucleases in the same antimutagenic pathway.
MOLECULAR AND CELLULAR BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Lisa Schubert, Ivo A. Hendriks, Emil P. T. Hertz, Wei Wu, Selene Selles-Baiget, Saskia Hoffmann, Keerthana Stine Viswalingam, Irene Gallina, Satyakrishna Pentakota, Bente Benedict, Joachim Johansen, Katja Apelt, Martijn S. Luijsterburg, Simon Rasmussen, Michael Lisby, Ying Liu, Michael L. Nielsen, Niels Mailand, Julien P. Duxin
Summary: This study reveals an essential role of SCAI in ensuring error-free ICL repair upon activation of the FA pathway. SCAI forms a complex with Pol zeta and localizes to ICLs during DNA replication. In the absence of SCAI, HR-mediated ICL repair is defective, resulting in deletions and radial chromosomes.
Review
Biochemistry & Molecular Biology
Joerg Fahrer, Markus Christmann
Summary: Nitrosamines, which are alkylating agents, are widely present in food, drinking water, cosmetics, and tobacco smoke, and can also be produced endogenously. Recently, nitrosamines have been found as impurities in various drugs, raising concerns due to their genotoxic and carcinogenic properties. In this article, we summarize the sources and chemical nature of alkylating agents, particularly relevant nitrosamines, and then discuss the DNA repair pathways involved in the protection against the genotoxic and carcinogenic effects of these compounds, including base excision repair, direct damage reversal by MGMT and ALKBH, nucleotide excision repair, and DNA translesion synthesis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Oncology
Ashlynn Ai Li Ler, Michael P. Carty
Summary: DNA damage tolerance pathways play a crucial role in allowing replication to proceed in the presence of lesions. Bypassing DNA lesions by TLS polymerases can lead to mutagenesis and cancer development, while homology-directed DDT allows error-free lesion bypass. Understanding these pathways can provide therapeutic avenues.
FRONTIERS IN ONCOLOGY
(2022)
Review
Genetics & Heredity
Richard D. Wood, Sylvie Doublie
Summary: DNA polymerase theta (Pol theta) is a DNA repair enzyme that plays a crucial role in maintaining genome integrity and protecting DNA against deletions and loss of heterozygosity. However, the use of Pol theta for genome protection may result in the deletion or addition of a few nucleotides at the repair site. Inactivation of Pol theta can enhance cell sensitivity to DNA strand-breaking chemicals and radiation, making inhibitors of Pol theta potentially useful in treating cancers dependent on homologous recombination.
ANNUAL REVIEW OF GENETICS
(2022)
Article
Biochemistry & Molecular Biology
Shuming Zhang, Xue Xiao, Jingwei Kong, Ke Lu, Shuo-Xing Dou, Peng-Ye Wang, Lu Ma, Yuru Liu, Guohong Li, Wei Li, Huidong Zhang
Summary: Strand displacement DNA synthesis (SDDS) is a crucial step in DNA replication with complex kinetics. Experiments with magnetic tweezers show that the rate and processivity of SDDS are influenced by force and dNTP concentration. Moreover, GC content has a significant impact on the processivity and rate of SDDS and exonuclease activity.
Review
Biochemistry & Molecular Biology
Bruno Cesar Feltes
Summary: The seven xeroderma pigmentosum proteins (XPps) play essential roles in the nucleotide excision repair (NER) pathway, repairing DNA damage caused by ultraviolet light exposure. These proteins collaborate with other key players to ensure the smooth progression of NER steps. Reexamining the structures of these proteins is crucial in understanding NER accurately.
Review
Biochemistry & Molecular Biology
Yuchen He, Luyuan Zhang, Ruoyu Zhou, Yumin Wang, Hao Chen
Summary: DNA mismatch repair is a crucial pathway for maintaining genomic stability, and its deficiency can lead to microsatellite instability, affecting tumor growth. Immunotherapies targeting MMR can increase the burden of neoantigens in tumor cells and serve as predictors for sensitivity and drug resistance in immunotherapy.
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Umakanta Swain, Gilgi Friedlander, Urmila Sehrawat, Avital Sarusi-Portuguez, Ron Rotkopf, Charlotte Ebert, Tamar Paz-Elizur, Rivka Dikstein, Thomas Carell, Nicholas E. Geacintov, Zvi Livneh
Summary: TENT4A plays a critical role in regulating multiple biological pathways, specifically in translesion DNA synthesis, by modulating mRNA stability and translation of DNA polymerase eta and RAD18 E3 ligase. Additionally, TENT4A indirectly regulates RAD18 through the tumor suppressor CYLD and the long non-coding antisense RNA PAXIP1-AS2, leading to dysregulation of TLS in endometrial cancer genomes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Cell Biology
Facundo Ramos, Laura Duran, Mar Sanchez, Adrian Campos, David Hernandez-Villamor, Francisco Antequera, Andres Clemente-Blanco
Summary: This study uses genome-wide sequencing to quantitatively analyze the dynamics of DNA end resection, re-synthesis, and gene conversion in homologous recombination. The findings reveal the involvement of different factors in regulating the rate and symmetry of DNA re-synthesis, and the independence of gene conversion from MMR.
Article
Biochemistry & Molecular Biology
Shanzhi Wang, Kyeryoung Lee, Stephen Gray, Yongwei Zhang, Catherine Tang, Rikke B. Morrish, Elena Tosti, Johanna van Oers, Mohammad Ruhul Amin, Paula E. Cohen, Thomas MacCarthy, Sergio Roa, Matthew D. Scharff, Winfried Edelmann, Richard Chahwan
Summary: Exonuclease 1 (EXO1) plays important roles in DNA repair processes through its enzymatic and scaffolding functions. Its enzymatic role is crucial for error-free DNA repair pathways, while it has a more nuanced function in non-canonical repair pathways. EXO1 is important for somatic hypermutation and switch recombination, acting as both an enzyme and a scaffold. During meiosis, the structural function of EXO1 is critical. Additionally, both Exo1(DA/DA) and Exo1(-)(/)(-) mice have similar mortality rates and cancer predisposition, suggesting the significance of EXO1 in disease.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Genetics & Heredity
Jin Tang, Feng Tang, Linlin Zhao
Summary: DNA interstrand cross-links (ICLs) are lesions formed by a covalent bond between DNA strands that prevent their separation, which is necessary for DNA interpretation. Researchers have developed a simple method for preparing model ICL unhooked intermediates derived from abasic (AP) sites.
Article
Biology
Michael T. Kimble, Matthew J. Johnson, Mattie R. Nester, Lorraine S. Symington
Summary: Exo1 and Sgs1 are involved in long-range resection during HR, which is connected to the activation of the DNA damage checkpoint and the mobility of chromosomes.
Review
Biochemistry & Molecular Biology
Alexander A. Kruchinin, Alena V. Makarova
Summary: DNA polymerase theta belongs to the A family of DNA polymerases and plays a key role in DNA repair and damage tolerance, including double-strand break repair and DNA translesion synthesis. Pol theta is often overexpressed in cancer cells and promotes their resistance to chemotherapeutic agents. In this review, we discuss unique biochemical properties and structural features of Pol theta, its multiple roles in protection of genome stability and the potential of Pol theta as a target for cancer treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Tolkappiyan Premkumar, Lakshmi Paniker, Rhea Kang, Mathilde Biot, Ericka Humphrey, Honorine Destain, Isabella Ferranti, Iyinyeoluwa Okulate, Holly Nguyen, Vindhya Kilaru, Melissa Frasca, Parijat Chakraborty, Francesca Cole
Summary: In yeast, the stabilized 3' end annealed with the homolog is identified as the first detectible CO precursor, while in mice, the CO precursor may include asymmetric SEI-like intermediates and dHJs. Unlike yeast, MLH3 is structurally required to differentiate CO precursors into dHJs in mice. This study provides insights into the mechanism of CO formation and highlights both conservation and unique features of meiotic recombination in mice.
Review
Cell Biology
Brenna Osborne, Daniela Bakula, Michael Ben Ezra, Charlotte Dresen, Esben Hartmann, Stella M. Kristensen, Garik Mkrtchyan, Malte H. Nielsen, Michael A. Petr, Morten Scheibye-Knudsen
AGEING RESEARCH REVIEWS
(2020)
Article
Cell Biology
Garik V. Mkrtchyan, Kotb Abdelmohsen, Penelope Andreux, Ieva Bagdonaite, Nir Barzilai, Soren Brunak, Filipe Cabreiro, Rafael de Cabo, Judith Campisi, Ana Maria Cuervo, Marco Demaria, Collin Y. Ewald, Evandro Fei Fang, Richard Faragher, Luigi Ferrucci, Adam Freund, Carlos G. Silva-Garcia, Anastasia Georgievskaya, Vadim N. Gladyshev, David J. Glass, Vera Gorbunova, Aubrey de Grey, Wei-Wu He, Jan Hoeijmakers, Eva Hoffmann, Steve Horvath, Riekelt H. Houtkooper, Majken K. Jensen, Martin Borch Jensen, Alice Kane, Moustapha Kassem, Peter de Keizer, Brian Kennedy, Gerard Karsenty, Dudley W. Lamming, Kai-Fu Lee, Nanna MacAulay, Polina Mamoshina, Jim Mellon, Marte Molenaars, Alexey Moskalev, Andreas Mund, Laura Niedernhofer, Brenna Osborne, Heidi H. Pak, Andrey Parkhitko, Nuno Raimundo, Thomas A. Rando, Lene Juel Rasmussen, Carolina Reis, Christian G. Riedel, Anais Franco-Romero, Bjoern Schumacher, David A. Sinclair, Yousin Suh, Pam R. Taub, Debra Toiber, Jonas T. Treebak, Dario Riccardo Valenzano, Eric Verdin, Jan Vijg, Sergey Young, Lei Zhang, Daniela Bakula, Alex Zhavoronkov, Morten Scheibye-Knudsen
Article
Biochemistry & Molecular Biology
Cecy R. Xi, Arianna Di Fazio, Naveed Ahmed Nadvi, Karishma Patel, Michelle Sui Wen Xiang, Hui Emma Zhang, Chandrika Deshpande, Jason K. K. Low, Xiaonan Trixie Wang, Yiqian Chen, Christopher L. D. McMillan, Ariel Isaacs, Brenna Osborne, Ana Julia Vieira de Ribeiro, Geoffrey W. McCaughan, Joel P. Mackay, W. Bret Church, Mark D. Gorrell
Article
Multidisciplinary Sciences
Jon Ambaek Durhuus, Maarten P. Rozing, Marie Krogh Nielsen, Christopher Rue Molbech, Guido Keijzers, Morten Scheibye-Knudsen, Lene Juel Rasmussen, Rudi G. J. Westendorp, Torben Lykke Sorensen
Summary: The study found no evidence supporting the hypothesis that A2E contributes to heightened inflammatory activity in age-related macular degeneration (AMD).
SCIENTIFIC REPORTS
(2021)
Article
Biology
Michael A. Petr, Irene Alfaras, Melissa Krawcyzk, Woei-Nan Bair, Sarah J. Mitchell, Christopher H. Morrell, Stephanie A. Studenski, Nathan L. Price, Kenneth W. Fishbein, Richard G. Spencer, Morten Scheibye-Knudsen, Edward G. Lakatta, Luigi Ferrucci, Miguel A. Aon, Michel Bernier, Rafael de Cabo
Summary: The study found that aging and frailty are associated with declines in gait speed, increased energetic cost of physical activity, and decreased working capacity. Aging and functional decline prompt organs to rewire their metabolism towards redox-related pathways.
Article
Neurosciences
Alexandra Boyko, Polina Tsepkova, Vasily Aleshin, Artem Artiukhov, Garik Mkrtchyan, Alexander Ksenofontov, Lyudmila Baratova, Sergey Ryabov, Anastasia Graf, Victoria Bunik
Summary: The study identifies significant mitochondrial lesions in the brain after severe spinal cord injury (SCI), with OGDHC being the most affected enzyme. Thiamine alleviates metabolic disturbances in the rat brain post-SCI, while TEGP shows limited effects. The regulation of OGDHC plays a key role in the chronic consequences of SCI, controlled by p53 and sirtuin 5.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2021)
Article
Cell Biology
Peng Song, Shaojun Liu, Dekang Liu, Guido Keijzers, Daniela Bakula, Shunlei Duan, Niels de Wind, Zilu Ye, Sergey Y. Vakhrushev, Morten Scheibye-Knudsen, Lene Juel Rasmussen
Summary: DNA mismatch repair (MMR) is an important DNA repair pathway that, when defective, is linked to carcinogenesis and drug resistance. This study demonstrates that depletion of CNOT6, which is overexpressed in cancer cells, sensitizes cells to DNA damage and enhances apoptosis. Depletion of CNOT6 also upregulates MMR and decreases mutation frequency, possibly through stabilizing mRNA transcripts from MMR genes and increasing MMR protein expression.
Article
Biochemistry & Molecular Biology
Brenna Osborne, Jane Reznick, Lauren E. Wright, David A. Sinclair, Gregory J. Cooney, Nigel Turner
Summary: This study investigated the effects of liver-specific SIRT3 overexpression on mitochondrial function and metabolism. The results showed that overexpression of SIRT3 increased oxygen consumption and reduced triglyceride accumulation. However, increasing hepatic SIRT3 had limited overall benefits during the development of diet-induced insulin resistance.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Cell Biology
Garik Mkrtchyan, Alexander Veviorskiy, Evgeny Izumchenko, Anastasia Shneyderman, Frank W. Pun, Ivan Ozerov, Alex Aliper, Alex Zhavoronkov, Morten Scheibye-Knudsen
Summary: In this study, the artificial intelligence-driven PandaOmics platform was used to analyze gene expression changes in rare DNA repair-deficient disorders and identify novel cancer targets. The researchers found that CEP135 was commonly downregulated in DNA repair diseases with high cancer predisposition, and high CEP135 expression was significantly associated with lower survival in sarcoma. Further investigation revealed PLK1 as a potential therapeutic candidate for sarcoma patients with high CEP135 levels and poor survival.
CELL DEATH & DISEASE
(2022)
Article
Endocrinology & Metabolism
Brenna Osborne, Lauren E. Wright, Amanda E. Brandon, Ella Stuart, Lewin Small, Joris Hoeks, Patrick Schrauwen, David A. Sinclair, Magdalene K. Montgomery, Gregory J. Cooney, Nigel Turner
Summary: This study investigated whether specific overexpression of SIRT3 in skeletal muscle could prevent high-fat diet-induced muscle insulin resistance. The results showed that overexpression of SIRT3 did not alleviate muscle insulin resistance induced by high-fat diet and intramuscular triglyceride content was increased. These findings indicate that muscle-specific overexpression of SIRT3 has only minor effects on the acute development of skeletal muscle insulin resistance in high-fat-fed rats.
JOURNAL OF ENDOCRINOLOGY
(2023)
Article
Biology
Alejandro Sola-Garcia, Maria Angeles Caliz-Molina, Isabel Espadas, Michael Petr, Concepcion Panadero-Moron, Daniel Gonzalez-Moran, Maria Eugenia Martin-Vazquez, Alvaro Jesus Narbona-Perez, Livia Lopez-Noriega, Guillermo Martinez-Corrales, Raul Lopez-Fernandez-Sobrino, Lina M. Carmona-Marin, Enrique Martinez-Force, Oscar Yanes, Maria Vinaixa, Daniel Lopez-Lopez, Jose Carlos Reyes, Joaquin Dopazo, Franz Martin, Benoit R. Gauthier, Morten Scheibye-Knudsen, Vivian Capilla-Gonzalez, Alejandro Martin-Montalvo
Summary: A multiomic approach reveals that long-term exposure to the Acly inhibitor SB-204990 can modulate molecular mechanisms associated with aging. ATP-citrate lyase has a crucial role in cellular metabolism, integrating the protein, carbohydrate, and lipid metabolism. In vivo studies using untargeted metabolomics, transcriptomics, and proteomics show that SB-204990 regulates energy metabolism, mitochondrial function, mTOR signaling, and folate cycle, and can prevent the development of metabolic abnormalities associated with an unhealthy diet.
COMMUNICATIONS BIOLOGY
(2023)
Article
Cell Biology
Indra Heckenbach, Garik V. Mkrtchyan, Michael Ben Ezra, Daniela Bakula, Jakob Sture Madsen, Malte Hasle Nielsen, Denise Oro, Brenna Osborne, Anthony J. Covarrubias, M. Laura Idda, Myriam Gorospe, Laust Mortensen, Eric Verdin, Rudi Westendorp, Morten Scheibye-Knudsen
Summary: A deep learning predictor based on nuclear morphology can identify senescent cells and is associated with health outcomes in humans.
Correction
Endocrinology & Metabolism
Anthony J. Covarrubias, Abhijit Kale, Rosalba Perrone, Jose Alberto Lopez-Dominguez, Angela Oliveira Pisco, Herbert G. Kasler, Mark S. Schmidt, Indra Heckenbach, Ryan Kwok, Christopher D. Wiley, Hoi-Shan Wong, Eddy Gibbs, Shankar S. Iyer, Nathan Basisty, Qiuxia Wu, Ik-Jung Kim, Elena Silva, Kaitlyn Vitangcol, Kyong-Oh Shin, Yong-Moon Lee, Rebeccah Riley, Issam Ben-Sahra, Melanie Ott, Birgit Schilling, Morten Scheibye-Knudsen, Katsuhiko Ishihara, Stephen R. Quake, John Newman, Charles Brenner, Judith Campisi, Eric Verdin
Summary: A correction to this paper has been published and can be accessed via a link at the top of the paper.
Meeting Abstract
Gastroenterology & Hepatology
C. Xi, A. Di Fazio, N. Nadvi, M. Xiang, H. Zhang, C. Deshpande, X. Wang, Y. Chen, B. Osborne, M. Tabar, X. Wang, C. Bailey, K. Patel, J. Mackay, G. Mccaughan, B. Church, M. Gorrell
JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY
(2020)
