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
Cell Biology
Yunshang Chen, Xiaohua Jie, Biyuan Xing, Zilong Wu, Xijie Yang, Xinrui Rao, Yingzhuo Xu, Dong Zhou, Xiaorong Dong, Tao Zhang, Kunyu Yang, Zhenyu Li, Gang Wu
Summary: This study found that the expression of REV1 was significantly upregulated in lung cancer tissues and associated with poor prognosis. Silencing REV1 reduced the growth and proliferation capacity of lung cancer cells. A REV1 inhibitor, JH-RE-06, effectively suppressed lung tumorigenesis.
CELL DEATH & DISEASE
(2022)
Article
Genetics & Heredity
James P. Wells, Emily Yun-Chia Chang, Leticia Dinatto, Justin White, Stephanie Ryall, Peter C. Stirling
Summary: DNA replication is a vulnerable time for genome stability maintenance. This study reveals that RAD18 plays a crucial role in coordinating DNA damage tolerance pathways, preventing transcription-replication conflicts, and stabilizing DNA:RNA hybrids during replication. Failure to recruit FANCD2 protein at difficult to replicate and R-loop prone sites leads to increased transcription-replication conflicts and DNA double strand breaks.
Article
Biochemistry & Molecular Biology
Aldo Spanjaard, Ronak Shah, Daniel de Groot, Olimpia Alessandra Buoninfante, Ben Morris, Cor Lieftink, Colin Pritchard, Lisa M. Zurcher, Shirley Ormel, Joyce J. Catsman, Renske De Korte-Grimmerink, Bjorn Siteur, Natalie Proost, Terry Boadum, Marieke van de Ven, Ji-Ying Song, Maaike Kreft, Paul C. M. van den Berk, Roderick L. Beijersbergen, Heinz Jacobs
Summary: PCNA-ubiquitination and REV1 play distinct roles in DNA damage tolerance, particularly in tolerating cisplatin lesions. Polymerase Kappa is essential in tolerating multiple genotoxic lesions, including cisplatin lesions.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Cell Biology
Longhao Wang, Tao Hu, Zhibo Shen, Yuanyuan Zheng, Qishun Geng, Lifeng Li, Beibei Sha, Miaomiao Li, Yaxin Sun, Yongjun Guo, Wenhua Xue, Dan Xuan, Ping Chen, Jie Zhao
Summary: The study revealed that targeting the deubiquitinating enzyme USP1 may be a potential strategy for the treatment of hepatocellular carcinoma (HCC). The USP1 inhibitor ML-323 inhibited the growth of HCC cells and induced cell cycle arrest. ML-323 treatment resulted in the accumulation of ubiquitinated proteins, induction of endoplasmic reticulum stress, and Noxa-dependent apoptosis. Additionally, active endoplasmic reticulum stress induced protective autophagy through AMPK phosphorylation.
CELL DEATH & DISEASE
(2022)
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
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
Biochemistry & Molecular Biology
Matthew Nolan, Kenneth Knudson, Marina K. Holz, Indrajit Chaudhury
Summary: mTOR interacts and cooperates with FANCD2 during replication stress to provide cellular stability, mediate stalled replication fork restart, and prevent nucleolytic degradation of the nascent DNA strands. This study reveals a novel functional cross-talk between the mTOR and FA DNA repair pathways to ensure genomic stability.
Review
Biochemistry & Molecular Biology
Winnie Tan, Andrew J. Deans
Summary: The Fanconi Anemia (FA) pathway maintains genome stability by preventing DNA damage, with the FA core complex playing a central role in monoubiquitination of FANCI-FANCD2. Any mutations in the FA core complex can lead to defective monoubiquitination, resulting in various phenotypes including DNA damage sensitivity, birth defects, early-onset bone marrow failure, and cancer.
PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Juan A. Cantres-Velez, Justin L. Blaize, David A. Vierra, Rebecca A. Boisvert, Jada L. Garzon, Benjamin Piraino, Winnie Tan, Andrew J. Deans, Niall G. Howlett
Summary: This study identifies a cyclin-dependent kinase (CDK) regulatory phosphosite (S592) proximal to the site of FANCD2 monoubiquitination, the phosphorylation of which affects the function of FANCD2 and mitotic fidelity. Mutation of S592 leads to abrogated monoubiquitination of FANCD2 during the S phase, affecting cell proliferation and mitotic fidelity.
MOLECULAR AND CELLULAR BIOLOGY
(2021)
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
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.
Article
Biology
Marina Schrecker, Juan C. Castaneda, Sujan Devbhandari, Charanya Kumar, Dirk Remus, Richard K. Hite
Summary: The research discovered that PCNA can adopt both open and closed conformations in the RFC:PCNA:DNA complex, allowing for direct insertion of dsDNA. Additionally, the study revealed that the RFC-catalyzed loading of PCNA onto DNA involves multiple steps, with partial melting facilitating lateral insertion into the central RFC:PCNA channel.
Article
Biochemistry & Molecular Biology
Md Kawsar Mustofa, Yuki Tanoue, Mami Chirifu, Tatsuya Shimasaki, Chie Tateishi, Teruya Nakamura, Satoshi Tateishi
Summary: RAD18 plays a crucial role in DNA damage repair by promoting DNA damage-driven signaling and recruiting DNA repair proteins through ubiquitination.
JOURNAL OF BIOCHEMISTRY
(2021)
