Article
Biochemistry & Molecular Biology
Richard O. Adeyemi, Nicholas A. Willis, Andrew E. H. Elia, Connor Clairmont, Shibo Li, Xiaohua Wu, Alan D. D'Andrea, Ralph Scully, Stephen J. Elledge
Summary: Protexin complex, including the REV3 polymerase, establishes a novel fork protection pathway that counteracts fork resection, particularly at ICL stalled forks. This pathway acts independently of BRCA/RAD51-mediated fork stabilization and is crucial for maintaining genomic stability.
Review
Genetics & Heredity
Masamichi Ishiai
Summary: The Fanconi anemia (FA) DNA repair pathway is activated through monoubiquitination of FANCD2 and its binding partner FANCI, regulated by the ATR kinase. This process serves as a good example of ATR's contribution to genome stability.
Article
Medicine, Research & Experimental
Pingping Xu, Danfeng Sun, Yaqi Gao, Yi Jiang, Ming Zhong, Gang Zhao, Jinxian Chen, Zheng Wang, Qiang Liu, Jie Hong, Haoyan Chen, Ying-Xuan Chen, Jing-Yuan Fang
Summary: Through whole-exome sequencing, we identified mutations in genes related to the Fanconi anemia DNA repair pathway in familial colorectal cancer patients, including CHEK2. Further experiments showed that CHEK2 plays a crucial role in cell cycle and DNA damage repair processes.
Article
Medicine, Research & Experimental
Wei Wei, Fangfang Shi, Yang Xu, Yang Jiao, Ying Zhang, Qiuxiang Ou, Xue Wu, Lingyi Yang, Jinhuo Lai
Summary: Next-generation sequencing was used to investigate molecular features in NSCLC patients with pathogenic/likely pathogenic ATM/ATR mutations. The results were validated using an external cohort of NSCLC patients.
JOURNAL OF TRANSLATIONAL MEDICINE
(2023)
Review
Cell Biology
Yeldar Baiken, Damira Kanayeva, Sabira Taipakova, Regina Groisman, Alexander A. Ishchenko, Dinara Begimbetova, Bakhyt Matkarimov, Murat Saparbaev
Summary: Complex DNA damage (CDD) is challenging to repair due to its complex structure compared to singular lesions, and if left unrepaired, can lead to serious consequences such as chromosomal rearrangements and genome instability. Repair of CDD requires the concurrent involvement of multiple DNA repair pathways to ensure effective repair.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Cell Biology
Yoko Katsuki, Masako Abe, Seon Young Park, Wenwen Wu, Hiromasa Yabe, Miharu Yabe, Haico van Attikum, Shinichiro Nakada, Tomohiko Ohta, Michael M. Seidman, Yonghwan Kim, Minoru Takata
Summary: RNF168 plays a critical role in recruiting SLX4 to ICL damage sites and is epistatic with SLX4 in promoting MMC tolerance.
Editorial Material
Cell Biology
Jasmine D. Peake, Kalisse I. Horne, Chiaki Noguchi, John P. Gilligan, Eishi Noguchi
Summary: Alcohol can cause cellular accumulation of acetaldehyde, a major carcinogen, and individuals with deficiency in acetaldehyde detoxification or the Fanconi anemia DNA repair pathway have an increased risk of esophageal squamous-cell carcinoma. This study reveals that acetaldehyde induces DNA damage at the replication fork, leading to replication stress and activation of cell cycle checkpoints. It also demonstrates that the p53 DNA damage response is elevated in response to acetaldehyde and the FA pathway limits genomic instability. These findings highlight the importance of the FA pathway and p53 DNA damage response in protecting against genomic instability and esophageal carcinogenesis.
Article
Biotechnology & Applied Microbiology
Hannah I. Ghasemi, Julien Bacal, Amanda C. Yoon, Katherine U. Tavasoli, Carmen Cruz, Jonathan T. Vu, Brooke M. Gardner, Chris D. Richardson
Summary: The efficiency of gene editing via homology-directed repair (HDR) can be enhanced by covalently modifying the template DNA to form interstrand crosslinks. These crosslinked templates (xHDRTs) significantly increase Cas9-mediated editing efficiencies in various cell types. The increased editing from xHDRTs is dependent on events occurring on the template molecule and requires the ATR kinase and components of the Fanconi anemia pathway.
NATURE BIOTECHNOLOGY
(2023)
Review
Reproductive Biology
Jingyu Zhao, Yixin Zhang, Wenbo Li, Mengmeng Yao, Chuqi Liu, Zihan Zhang, Caiqin Wang, Xiaomei Wang, Kai Meng
Summary: The Fanconi anemia pathway plays a key role in repairing DNA interstrand crosslinking damage, and it is closely related to premature ovarian insufficiency.
BIOLOGY OF REPRODUCTION
(2023)
Article
Oncology
Jemina Lehto, Anna Huguet Ninou, Dimitrios Chioureas, Jos Jonkers, Nina M. S. Gustafsson
Summary: Chemotherapeutics that introduce DNA crosslinks, like platinum drugs, are used to treat cancers but face limitations due to side effects and acquired resistance. Targeting DNA repair, particularly the interaction between CX3CR1 and the FA repair pathway, holds promise in improving treatment responses and reducing side effects.
Article
Multidisciplinary Sciences
Jessica W. Luzwick, Eszter Dombi, Rebecca A. Boisvert, Sunetra Roy, Soyoung Park, Selvi Kunnimalaiyaan, Steffi Goffart, Detlev Schindler, Katharina Schlacher
Summary: The Fanconi anemia suppressor genes in mitochondria protect mtDNA replication forks, while degradation by MRE11 nuclease leads to loss of nascent mtDNA. Unlike nuclear DNA replication fork stability, mitochondrial replication fork protection does not require pathway activation, revealing a separation between the two stability pathways.
Article
Biochemistry & Molecular Biology
Gijs Zonderland, Riccardo Vanzo, Sampath Amitash, Elena Martin-Doncel, Fabian Coscia, Andreas Mund, Mads Lerdrup, Jan Benada, Dominik Boos, Luis Toledo
Summary: In contrast to existing models, the TRESLIN-MTBP complex can prevent premature entry into G2 independently of ATR/CHK1 kinases in early S-phase. It acts as a monitoring system that checks the activation of replication forks and senses the rate of origin firing to prevent premature entry into G2.
Article
Oncology
Anna Huguet Ninou, Jemina Lehto, Dimitrios Chioureas, Hannah Stigsdotter, Korbinian Schelzig, Emma Akerlund, Greta Gudoityte, Ulrika Joneborg, Joseph Carlson, Jos Jonkers, Brinton Seashore-Ludlow, Nina Marie Susanne Gustafsson
Summary: DNA-damaging chemotherapeutics, such as platinum drugs, rely on the DNA repair capacity of cancer cells for efficacy, but cancer cells often develop resistance by altering their DNA damage response pathways. Targeting PFKFB3, which is commonly overexpressed in cancer, sensitizes cancer cells to platinum drugs and improves treatment efficacy by modulating the Fanconi anemia DNA repair pathway. Inhibition of PFKFB3 disrupts the assembly of key FA repair factors, prevents fork restart, and ultimately leads to an accumulation of DNA damage in replicating cells and fork collapse, enhancing the effectiveness of ICL-inducing cancer treatments.
Article
Environmental Sciences
Yun Zhao, Linqing Wei, Abderrahmane Tagmount, Alex Loguinov, Amin Sobh, Alan Hubbard, Cliona M. McHale, Christopher J. Chang, Chris D. Vulpe, Luoping Zhang
Summary: This study identified genes affecting formaldehyde toxicity in human hematopoietic cells using CRISPR screening, including those that increase sensitivity and resistance, along with related pathways and mechanisms. Results indicated a significant role for formaldehyde metabolism and the Fanconi anemia pathway in toxicity tolerance, and new network analyses revealed potential roles for one-carbon metabolism, fatty acid synthesis, and mTOR signaling in modulating formaldehyde toxicity.
Article
Cell Biology
Riko Ishimoto, Yota Tsuzuki, Tomoki Matsumura, Seiichiro Kurashige, Kouki Enokitani, Koki Narimatsu, Mitsunori Higa, Nozomi Sugimoto, Kazumasa Yoshida, Masatoshi Fujita
Summary: The study reveals that the accumulation of ssDNA and DDR proteins is induced by site-specific replication fork barriers on the human chromosome. SLX4-XPF acts as an upstream factor for the accumulation of DDR proteins, leading to the recruitment of ATR and FANCD2. Lac! binding in S phase results in underreplication and abnormal mitotic segregation of the lac) arrays. The SLX4-ATR axis represses anaphase abnormality induced by Lac! binding.
JOURNAL OF CELL BIOLOGY
(2021)
Article
Genetics & Heredity
Frank X. Donovan, Avani Solanki, Minako Mori, Niranjan Chavan, Merin George, Selvaa C. Kumar, Yusuke Okuno, Hideki Muramastsu, Kenichi Yoshida, Akira Shimamoto, Akifumi Takaori-Kondo, Hiromasa Yabe, Seishi Ogawa, Seiji Kojima, Miharu Yabe, Ramanagouda Ramanagoudr-Bhojappa, Agata Smogorzewska, Sheila Mohan, Aruna Rajendran, Arleen D. Auerbach, Minoru Takata, Settara C. Chandrasekharappa, Babu Rao Vundinti
Review
Cell Biology
John K. Eykelenboom, Tomoyuki U. Tanaka
Article
Hematology
Yusuke Okamoto, Masako Abe, Anfeng Mu, Yasuko Tempaku, Colette B. Rogers, Ayako L. Mochizuki, Yoko Katsuki, Masato T. Kanemaki, Akifumi Takaori-Kondo, Alexandra Sobeck, Anja-Katrin Bielinsky, Minoru Takata
Summary: Fanconi anemia (FA) is a hereditary disorder caused by mutations in any 1 of 22 FA genes. Recent studies have shown that the DNA/RNA helicase SLFN11 plays a role in cell death sensitivity to chemotherapeutic treatments in cancer cells. The depletion of SLFN11 has been shown to improve cell survival in FA patient-derived cells, suggesting a potential link between SLFN11 and FA pathophysiology.
Article
Biology
Yuki Sakamoto, Tetsuya Kokuta, Ai Teshigahara, Kenta Iijima, Hiroyuki Kitao, Minoru Takata, Hiroshi Tauchi
Summary: The repair pathway choice for DNA double-strand breaks is dependent on cell cycle phases, with homologous recombination repair most active in the S phase; unexpectedly, significant homology directed repair activity was also observed during mitosis.
JOURNAL OF RADIATION RESEARCH
(2021)
Article
Hematology
Anfeng Mu, Asuka Hira, Akira Niwa, Mitsujiro Osawa, Kenichi Yoshida, Minako Mori, Yusuke Okamoto, Kazuko Inoue, Keita Kondo, Masato T. Kanemaki, Tomonari Matsuda, Etsuro Ito, Seiji Kojima, Tatsutoshi Nakahata, Seishi Ogawa, Keigo Tanaka, Keitaro Matsuo, Megumu K. Saito, Minoru Takata
Summary: A novel Fanconi anemia-like inherited bone marrow failure syndrome has been discovered in Japanese children and is associated with variants in the ADH5 and ALDH2 genes. ADH5 is identified as the primary defense against formaldehyde, with ALDH2 providing a backup mechanism. Patient-derived fibroblasts displayed normal levels of DNA repair, whereas disease model iPSCs showed defective cell expansion during hematopoietic differentiation in vitro, which could be partially reversed by treatment with a new small molecule called C1.
Article
Oncology
Junhong Guan, Changzheng Lu, Qihuang Jin, Huiming Lu, Xiang Chen, Lei Tian, Yanbin Zhang, Janice Ortega, Junqiu Zhang, Silvia Siteni, Mingyi Chen, Liya Gu, Jerry W. Shay, Anthony J. Davis, Zhijian J. Chen, Yang-Xin Fu, Guo-Min Li
Summary: This study revealed that loss of MutLa subunit MLH1 leads to production of neoantigens and activation of the cGAS-STING pathway, affecting DNA repair process and ultimately causing chromosomal abnormalities and DNA release. This unknown MMR mechanism has significant implications for genome stability and cancer therapy.
Article
Biochemistry & Molecular Biology
Xinlin Xu, Yixi Xu, Ruiyuan Guo, Ran Xu, Congcong Fu, Mengtan Xing, Hiroyuki Sasanuma, Qing Li, Minoru Takata, Shunichi Takeda, Rong Guo, Dongyi Xu
Summary: Cell-based, in vitro and in vivo assays demonstrate that Fanconi anemia factors participate in a BRCA1-dependent BIR-like pathway, aiding in the restarting of stalled replication forks, while persistent replication stress contributes to FA pathogenesis. This suggests that the FA pathway is one of the BIR-like pathways and replication stress plays a crucial role in FA disease progression.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Yusheng Zhang, Tong Liu, Fenghua Yuan, Liliana Garcia-Martinez, Kyutae D. Lee, Stephanie Stransky, Simone Sidoli, Ramiro E. Verdun, Yanbin Zhang, Zheng Wang, Lluis Morey
Summary: Studying the role of RING1B, a core component of Poly-comb Repressive Complex 1, in the enhancer-promoter interaction and gene activation revealed its key role in regulating R-loop formation and RNA Pol II activity. The recruitment of RING1B to estrogen-activated genes is dependent on both estrogen receptor alpha (ER alpha) and RNA. These findings highlight the functional interplay between RING1B, RNA and ER alpha in safeguarding chromatin architecture and regulating oncogenic programs.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Cell Biology
Yoko Katsuki, Masako Abe, Seon Young Park, Wenwen Wu, Hiromasa Yabe, Miharu Yabe, Haico van Attikum, Shinichiro Nakada, Tomohiko Ohta, Michael M. Seidman, Yonghwan Kim, Minoru Takata
Summary: RNF168 plays a critical role in recruiting SLX4 to ICL damage sites and is epistatic with SLX4 in promoting MMC tolerance.
Article
Multidisciplinary Sciences
Koichi Sato, Nerea Martin-Pintado, Harm Post, Maarten Altelaar, Puck Knipscheer
Summary: The study reveals a three-step mechanism for G4 unwinding, ensuring stability during DNA replication. This mechanism allows for efficient handling of G4 structures during DNA replication, thereby preventing genome instability.
Article
Cell Biology
Minoru Takata, Hiroshi Harada
Summary: Ataxia-telangiectasia (A-T) is a rare genetic disease that affects multiple organ systems and increases the risk of cancer and immunodeficiency. The 19th Ataxia-Telangiectasia Workshop 2023 (ATW2023) was successfully held in Kyoto, with over 150 participants from around the world, despite the ongoing COVID-19 pandemic. This meeting report highlights the key points of the conference and acknowledges the financial support from the Molecular Biology Society of Japan (MBSJ).
Article
Chemistry, Physical
Jiuyan Chen, Fang Li, Jun Gu, Xiao Zhang, Mattia Bartoli, Justin B. Domena, Yiqun Zhou, Wei Zhang, Victor Paulino, Braulio C. L. B. Ferreira, Nicholas Michael Brejcha, Liang Luo, Chiara Arduino, Fulvia Verde, Fangliang Zhang, Fuwu Zhang, Alberto Tagliaferro, Jean-Hubert Olivier, Yanbin Zhang, Roger M. Leblanc
Summary: In this study, cationic carbon dots (Y15-CDs) derived from a drug (Y15) were prepared and shown to bind with DNA through electrostatic interactions and partial intercalation. Y15-CDs were found to possess nucleus targeting and anticancer abilities, exhibiting higher cytotoxicity to cancer cells compared to normal cells.
JOURNAL OF COLLOID AND INTERFACE SCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Clement Rouillon, Bruna Eckhardt, Leonie Kollenstart, Fabian Gruss, Alexander E. E. Verkennis, Inge Rondeel, Peter H. L. Krijger, Giulia Ricci, Alva Biran, Theo van Laar, Charlotte M. Delvaux de Fenffe, Georgiana Luppens, Pascal Albanese, Koichi Sato, Richard A. Scheltema, Wouter de Laat, Puck Knipscheer, Nynke H. Dekker, Anja Groth, Francesca Mattiroli
Summary: During cell cycle, CAF-1 plays a crucial role in chromatin replication, and its interaction with the DNA replication machinery remains unknown. The study reveals that the interaction between CAF-1 and replication forks differs between the leading and lagging strand. Biochemical reconstructions demonstrate that DNA and histones promote CAF-1 recruitment to its binding partner PCNA, and two CAF-1 complexes are required for efficient nucleosome assembly. In the context of the replisome, CAF-1 competes with Pol epsilon for PCNA binding on the leading strand, while it does not affect the activity of Pol delta on the lagging strand.
NUCLEIC ACIDS RESEARCH
(2023)
Review
Cell Biology
Tomoya Kujirai, Haruhiko Ehara, Shun-ichi Sekine, Hitoshi Kurumizaka
Summary: In eukaryotes, genomic DNA is packaged into chromatin and the nucleosome acts as a barrier to transcription. The RNA polymerase II elongation complex disassembles the nucleosome during transcription to allow passage. After transcription, the nucleosome is rebuilt by transcription-coupled nucleosome reassembly, which plays a crucial role in preserving epigenetic information. The histone chaperone FACT is involved in nucleosome disassembly, maintenance, and reassembly during transcription in chromatin. Recent structural studies have provided insights into the structural transitions of the nucleosome during transcription.
Article
Cell Biology
Fei Qi, Erin Alvi, Minori Ogawa, Junya Kobayashi, Anfeng Mu, Minoru Takata
Summary: The SLFN11 gene is involved in cell fate decision and contains the RNase domain and the helicase/ATPase domain. The contribution of these domains to the chemotherapeutic response is still debated. By expressing a SLFN11 mutant with mutations in critical residues for RNase activity, we found that this mutant still suppressed DNA damage tolerance, destabilized replication forks, and disrupted recruitment of the fork protector RAD51. On the other hand, we confirmed that the helicase domain was essential for accelerating fork degradation. The fork degradation caused by the RNase mutant depended on DNA2 and MRE11 nuclease, but not on the novel interactor FXR1. Collectively, these results indicate that the RNase domain function is dispensable for SLFN11-mediated cell fate decision during replication stress response.