Review
Biochemistry & Molecular Biology
Joanna Morcinek-Orlowska, Karolina Zdrojewska, Alicja Wegrazyn
Summary: DNA polymerases are enzymes that synthesize DNA and play important roles in DNA replication, repair, and genetic recombination. Phage-encoded DNA polymerases exhibit unique structural and functional properties, which are crucial for the survival of these viruses and can also be utilized in genetic engineering and biotechnology.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Verena Hurst, Kiran Challa, Felix Jonas, Romain Forey, Ragna Sack, Jan Seebacher, Christoph D. Schmid, Naama Barkai, Kenji Shimada, Susan M. Gasser, Jerome Poli
Summary: In budding yeast, the Mec1 kinase plays a crucial role in evicting RNAPII and RNAPIII to facilitate replication fork progression. The non-phosphorylatable mec1-S1991A mutant hinders replication fork progression and compromises survival on hydroxyurea. Disrupting chromatin-bound RNAPII can alleviate the lethality in mec1-S1991A mutants.
Article
Multidisciplinary Sciences
Sebastian Zeltzer, Pierce Longmire, Marek Svoboda, Giovanni Bosco, Felicia Goodrum
Summary: Human cells have multiple specialized DNA polymerases for chromosomal DNA synthesis and repair, while complex DNA viruses may rely on host polymerases for synthesis. This study shows that error-prone Y-family polymerases can restrict human cytomegalovirus genome synthesis, while other TLS polymerases are required for optimal replication. Host polymerases also suppress viral genome rearrangements, indicating their role in ensuring viral genome stability.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biology
Roman Jaksik, David A. A. Wheeler, Marek Kimmel
Summary: This study proposes a method of detecting ORI based on somatic mutation patterns caused by the mutator phenotype of damaged DNA polymerase epsilon (POLE), and identifies shared ORI locations in tumors through accumulated mutations. The study also compares the results from multiple detection methods and defines a consensus set of ORI. The results demonstrate the viability of mutation-based detection in determining ORI location and associated sequence features.
Review
Oncology
Ken-ichi Yoshioka, Yusuke Matsuno
Summary: This manuscript reviews the factors that increase the risk of genomic destabilization, including the cellular state that resembles senescence, and explores the pathways leading to this instability and associated mutagenesis, ultimately resulting in cancer development.
Article
Multidisciplinary Sciences
Tara Al Zubaidi, O. H. Fiete Gehrisch, Marie-Michelle Genois, Qi Liu, Shan Lu, Jong Kung, Yunhe Xie, Jan Schuemann, Hsiao-Ming Lu, Aaron N. Hata, Lee Zou, Kerstin Borgmann, Henning Willers
Summary: Mutant KRAS is a common driver gene in tumors and often results in resistance to anti-cancer treatments such as radiation. Proton radiation was found to be able to slow fork progression and induce fork stalling preferentially in KRAS mutant cells, partly reversing the radioresistance associated with mutant KRAS. The cellular effects of protons in the presence of KRAS mutation differ from other drugs affecting replication, highlighting the unique nature of the DNA damage caused by protons.
SCIENTIFIC REPORTS
(2021)
Review
Cell Biology
Shan Qiu, Guixing Jiang, Liping Cao, Jun Huang
Summary: Replication fork reversal is a critical protective mechanism in higher eukaryotic cells in response to replication stress, where forks change direction to form a Holliday junction-like structure for protection, with DNA damage repair proteins playing important roles.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Genetics & Heredity
Justin A. Ling, Zach Frevert, M. Todd Washington
Summary: DNA damage can cause replication forks to stall, but cells have evolved translesion synthesis polymerases to incorporate nucleotides opposite DNA lesions. Recent methodological developments, including time-lapse X-ray crystallography, full-ensemble hybrid methods, and cryo-electron microscopy, have enhanced our understanding of the structures and mechanisms of these polymerases.
Article
Biochemistry & Molecular Biology
Mohammad Hajjar, Nicholas Chim, Chao Liu, Piet Herdewijn, John C. Chaput
Summary: In this study, researchers used X-ray crystallography to investigate the recognition of pTNA nucleotides by polymerases. The findings reveal that the polymerase mediates base pairing between pTNA and DNA, providing new insights into the enzymatic synthesis of XNAs.
NUCLEIC ACIDS RESEARCH
(2022)
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
Anna V. Yudkina, Evgeniy S. Shilkin, Alena V. Makarova, Dmitry O. Zharkov
Summary: DNA-protein cross-links (DPCs) are bulky adducts that interfere with replication. In human cells, they are processed by SPRTN, a protease activated by DNA polymerases stuck at DPCs. Different DNA polymerases have different effects on DPCs depending on their locations.
Article
Multidisciplinary Sciences
Katerina Zabrady, Matej Zabrady, Peter Kolesar, Arthur W. H. Li, Aidan J. Doherty
Summary: CRISPR-Cas pathways provide acquired immunity against foreign genetic elements for prokaryotes. A family of CRISPR-Associated Primase-Polymerases (CAPPs) has been identified and characterized in prokaryotes, showing genetic and physical association with Cas1 and Cas2, as well as DNA-dependent DNA priming and polymerization activities. CAPPs may play key roles in CRISPR-Cas adaptation by forming bespoke complexes with Cas proteins.
NATURE COMMUNICATIONS
(2021)
Review
Biochemistry & Molecular Biology
David P. Millar
Summary: This article describes the smFRET methods used to probe the conformational dynamics of DNA polymerases, with a focus on E. coli DNA polymerase I. The studies reviewed reveal the conformational dynamics underlying the nucleotide selection, proofreading, and 5' nuclease activities of Pol I, which are likely employed across the DNA polymerase family. smFRET methods have also been used to examine other aspects of DNA polymerase activity.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Microbiology
Peter B. Bohall, Stephen D. Bell
Summary: The loss of putative repair polymerases PolB2 and/or PolB3 in the crenarchaeon Sulfolobus islandicus leads to a modest growth advantage and insensitivity to hydrogen peroxide. However, cells lacking PolB3 show enhanced sensitivity to the DNA damaging agent 4-NQO, suggesting that these non-essential DNA polymerases may influence DNA repair pathway choice in hyperthermophilic aerobes.
FRONTIERS IN MICROBIOLOGY
(2021)
Article
Multidisciplinary Sciences
Ke Zhang, Yang Sui, Wu-Long Li, Gen Chen, Xue-Chang Wu, Robert J. Kokoska, Thomas D. Petes, Dao-Qiong Zheng
Summary: The deficiency of Pol epsilon leads to genomic instability and multiple human diseases. Low levels of Pol epsilon result in cellular changes such as elevated rates of recombination, aneuploidy, contraction of ribosomal DNA repeats, shortened telomeres, increased break-induced replication, and higher rate of single-base mutations. Compared to other replicative DNA polymerases, Pol epsilon displays distinct patterns of genomic alterations.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Letter
Oncology
Jean-Sebastien Hoffmann
BULLETIN DU CANCER
(2021)
Article
Oncology
Melanie K. Prodhomme, Roxane M. Pommier, Camille Franchet, Frederique Fauvet, Valerie Bergoglio, Pierre Brousset, Anne-Pierre Morel, Anne-Cecile Brunac, Mojgan Devouassoux-Shisheboran, Virginie Petrilli, Caroline Moyret-Lalle, Jean-Sebastien Hoffmann, Alain Puisieux, Agnes Tissier
Summary: The study demonstrated that ZEB1 represses the expression of POLQ, inhibiting TMEJ activity and controlling genome integrity in breast cancer cells. This reveals an original mechanism of TMEJ regulation and highlights ZEB1 as a key player in maintaining genome stability during cancer progression.
Article
Biochemistry & Molecular Biology
Elisa Mentegari, Federica Bertoletti, Miroslava Kissova, Elisa Zucca, Silvia Galli, Giulia Tagliavini, Anna Garbelli, Antonio Maffia, Silvia Bione, Elena Ferrari, Fabrizio d'Adda di Fagagna, Sofia Francia, Simone Sabbioneda, Liuh-Yow Chen, Joachim Lingner, Valerie Bergoglio, Jean-Sebastien Hoffmann, Ulrich Hubscher, Emmanuele Crespan, Giovanni Maga
Summary: This study reveals that silencing human DNA polymerase (Pol lambda) in ALT cells represses ALT activity and induces telomeric stress, while replication stress in the absence of Pol lambda strongly affects the survival of ALT cells. Additionally, Pol lambda can promote annealing of telomeric repeats and is regulated by TERRA and replication protein A, with the POT1/TPP1 heterodimer stimulating Pol lambda activity.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Domenico Maiorano, Jana El Etri, Camille Franchet, Jean-Sebastien Hoffmann
Summary: Genome instability plays a crucial role in tumor formation and treatment, but excessive instability may suppress tumorigenesis and be associated with a better prognosis. Specialized DNA polymerases play a key role in reducing extreme genetic instability, helping to avoid or repair DNA damage.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Lilas Courtot, Elodie Bournique, Chrystelle Maric, Laure Guitton-Sert, Miguel Madrid-Mencia, Vera Pancaldi, Jean-Charles Cadoret, Jean-Sebastien Hoffmann, Valerie Bergoglio
Summary: This study reveals that low replication stress can lead to advanced DNA replication timing, which is cell-type specific and involves large heterochromatin domains. These advanced events can be inherited by the next generation of cells, leading to changes in chromatin accessibility, replication origin landscape, and gene expression.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Marina Dall'Osto, Laura Pierini, Nicolas Valery, Jean-Sebastien Hoffmann, Marie-Jeanne Pillaire
Summary: The study revealed a new role of Pol kappa in controlling the stability and abundance of checkpoint kinase 1 (Chk1), where loss of Pol kappa decreases Chk1 protein levels and protects it from proteasome degradation. Additionally, the fork restart defects in Pol kappa-depleted cells can be overcome by the reexpression of Chk1.
MOLECULAR AND CELLULAR BIOLOGY
(2021)
Article
Biology
Solenne Gaillard, Virginie Charasson, Cyril Ribeyre, Kader Salifou, Marie-Jeanne Pillaire, Jean-Sebastien Hoffmann, Angelos Constantinou, Didier Trouche, Marie Vandromme
Summary: KDM5A and KDM5B histone-demethylases play crucial roles in replication stress response and tolerance, positively regulating RRM2 and activated Chk1. They are major players in RS management, and drugs targeting their enzymatic activity may not fully address all cancer-related consequences of their overexpression.
Article
Oncology
Jian Li, Josephine Mun-Yee Ko, Wei Dai, Valen Zhuoyou Yu, Hoi Yan Ng, Jean-Sebastien Hoffmann, Maria Li Lung
Summary: High expression of POLQ in esophageal squamous cell carcinoma is associated with unfavorable prognosis, contributing to malignant phenotypes through promoting genome stability, suggesting it as a potential therapeutic target.
Review
Oncology
Camille Franchet, Jean-Sebastien Hoffmann, Florence Dalenc
Summary: PARP inhibitors are used to treat breast cancer with mutated BRCA1/2 HR factors due to their synthetic lethal effect with homologous recombination deficiency. Unfortunately, the high rate of PARP inhibitor resistance in clinical practice has dampened initial hopes. New strategies are being explored to overcome resistance mechanisms and improve the therapeutic index of PARP inhibitors.
Editorial Material
Cell Biology
Jean-Sebastien Hoffmann
Summary: The major challenge in DNA replication is to ensure the transmission of intact genetic material to daughter cells. Despite extensive research on the cellular responses to replication problems and their source, the transmission of genome modifications and their heritability in mitosis has been less documented. Recent studies have shown that low replication stress can impact the next generation of cells, transmitting DNA damage and altering the replication timing program of chromosomal domains in daughter cells. This progression of replication issues into mitosis and daughter cells may provide advantages by alerting cells to risky loci and offering an adaptive mechanism to anticipate future problems, especially in the context of cancer cell resistance to therapy.
Review
Cell Biology
Melanie K. Prodhomme, Sarah Pericart, Roxane M. Pommier, Anne-Pierre Morel, Anne-Cecile Brunac, Camille Franchet, Caroline Moyret-Lalle, Pierre Brousset, Alain Puisieux, Jean-Sebastien Hoffmann, Agnes Tissier
Summary: Breast cancer cells often have mutations in DNA repair genes, with overexpression of POLQ potentially leading to genetic instability. The specific increase in expression of POLQ is associated with a characteristic mutational signature, and its regulatory mechanism is related to the expression of transcription factors in breast tumor subtypes.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Genetics & Heredity
Daniel de Barcellos Azambuja, Helena de Castro e Gloria, Gabriel e Silva Montenegro, Antonio Nocchi Kalil, Jean-Sebastien Hoffmann, Natalia Motta Leguisamo, Jenifer Saffi
Summary: Through evaluating the gene expression in tumor specimens and healthy tissues of 63 colorectal cancer (CRC) patients, it was found that the MRE11 homologous recombination repair gene is significantly overexpressed in CRC, particularly in primary tumors of higher stages, and mostly in right-side CRC, which has the worst prognosis. Furthermore, high MRE11 expression is associated with shorter overall survival and higher risk of death. Therefore, monitoring MRE11 expression could serve as both a predictor of outcome and a marker for selecting treatments for CRC patients.
Article
Biochemistry & Molecular Biology
Guillaume Labrousse, Pierre Vande Perre, Genis Parra, Marion Jaffrelot, Laura Leroy, Frederic Chibon, Frederic Escudie, Janick Selves, Jean-Sebastien Hoffmann, Rosine Guimbaud, Malik Lutzmann
Summary: The exonuclease domain of DNA polymerases epsilon's catalytic subunit (POLE) plays a role in proofreading by removing misincorporated nucleotides. Certain mutations in the POLE exonuclease domain, such as N363K, not only increase single nucleotide substitutions but also cause DNA damage and chromosome instability. This study highlights the importance of assessing both the mutational potential and genetic instability for the classification and treatment of POLE-mutated tumors.
Article
Oncology
Pascale Palassin, Marion Lapierre, Sandrine Bonnet, Marie-Jeanne Pillaire, Balazs Gyorffy, Catherine Teyssier, Stephan Jalaguier, Jean-Sebastien Hoffmann, Vincent Cavailles, Audrey Castet-Nicolas
Summary: This study reveals that RIP140 plays a role in maintaining microsatellite stability through positively regulating the expression of the POLK gene. The regulation of POLK gene expression by RIP140 involves the p53 tumor suppressor. The correlation between RIP140 and POLK gene expression was observed in CRC patient samples. Furthermore, it was found that cells lacking the Rip140 gene had an increased cellular response to methyl methane sulfonate.
CANCER DRUG RESISTANCE
(2022)
Meeting Abstract
Oncology
Audrey Lumeau, Nicolas Bery, Cyril Ribeyre, Samad Elkaoutari, Guillaume Labrousse, Miguel Madrid-Mencia, Vera Pancaldi, Marie-Jeanne Pillaire, Valerie Bergoglio, Nelson Dusseti, Jean-Sebastien Hoffmann, Louis Buscail, Malik Lutzmann, Pierre Cordelier
