DNA Damage Response: Three Levels of DNA Repair Regulation
Bianca M. Sirbu,David Cortez +1 more
TLDR
This review focuses on three levels of regulation: phosphorylating repair proteins to modify their activities, initiating a complex series of changes in the local chromatin structure near the damage site, and altering the overall cellular environment to make it more conducive to repair.Abstract:
Genome integrity is challenged by DNA damage from both endogenous and environmental sources. This damage must be repaired to allow both RNA and DNA polymerases to accurately read and duplicate the information in the genome. Multiple repair enzymes scan the DNA for problems, remove the offending damage, and restore the DNA duplex. These repair mechanisms are regulated by DNA damage response kinases including DNA-PKcs, ATM, and ATR that are activated at DNA lesions. These kinases improve the efficiency of DNA repair by phosphorylating repair proteins to modify their activities, by initiating a complex series of changes in the local chromatin structure near the damage site, and by altering the overall cellular environment to make it more conducive to repair. In this review, we focus on these three levels of regulation to illustrate how the DNA damage kinases promote efficient repair to maintain genome integrity and prevent disease.read more
Citations
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The essential kinase ATR: ensuring faithful duplication of a challenging genome
TL;DR: This Review examines how the replication stress response that is controlled by the kinase ataxia telangiectasia and Rad3-related (ATR) senses and resolves threats to DNA integrity so that the DNA remains available to read in all of the authors' cells.
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Repair of double-strand breaks by end joining.
TL;DR: There is great interest in defining alt-N HEJ more precisely, including its regulation relative to c-NHEJ, in light of evidence that alt- NHEJ can execute chromosome rearrangements.
Journal ArticleDOI
DNA mismatch repair and the DNA damage response.
TL;DR: The role of DNA mismatch repair (MMR) in the DNA damage response (DDR) that triggers cell cycle arrest and, in some cases, apoptosis is discussed, including some encountered in widely used chemotherapy regimes.
Journal ArticleDOI
The core spliceosome as target and effector of non-canonical ATM signalling
Maria Tresini,Daniël O. Warmerdam,Petros Kolovos,Loes Snijder,Mischa G. Vrouwe,Jeroen Demmers,Wilfred F. J. van IJcken,Frank Grosveld,René H. Medema,Jan H.J. Hoeijmakers,Leon H.F. Mullenders,Wim Vermeulen,Jurgen A. Marteijn +12 more
TL;DR: It is shown that transcription-blocking DNA lesions promote chromatin displacement of late-stagespliceosomes and initiate a positive feedback loop centred on the signalling kinase ATM, which signals to impede spliceosome organization further and augment ultraviolet-irradiation-triggered alternative splicing at the genome-wide level.
Journal ArticleDOI
Identification of Proteins at Active, Stalled, and Collapsed Replication Forks Using Isolation of Proteins on Nascent DNA (iPOND) Coupled with Mass Spectrometry
Bianca M. Sirbu,W. Hayes McDonald,Huzefa Dungrawala,Akosua Badu-Nkansah,Gina Kavanaugh,Yaoyi Chen,David L. Tabb,David Cortez +7 more
TL;DR: In this article, the authors combined isolation of proteins on nascent DNA (iPOND) with quantitative mass spectrometry to identify important replication and stress response proteins, and identified 290 proteins enriched on newly replicated DNA at active, stalled, and collapsed replication forks.
References
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Journal ArticleDOI
The DNA Damage Response: Making It Safe to Play with Knives
TL;DR: This review will focus on how the DDR controls DNA repair and the phenotypic consequences of defects in these critical regulatory functions in mammals.
Journal ArticleDOI
ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage
Shuhei Matsuoka,Bryan A. Ballif,Agata Smogorzewska,Agata Smogorzewska,E. Robert McDonald,Kristen E. Hurov,Ji Luo,Corey E. Bakalarski,Zhenming Zhao,Nicole L. Solimini,Yaniv Lerenthal,Yosef Shiloh,Steven P. Gygi,Stephen J. Elledge +13 more
TL;DR: A large-scale proteomic analysis of proteins phosphorylated in response to DNA damage on consensus sites recognized by ATM and ATR is performed and more than 900 regulated phosphorylation sites encompassing over 700 proteins are identified.
Journal ArticleDOI
ATM and related protein kinases: safeguarding genome integrity
TL;DR: Understanding ATM's mode of action provides new insights into the association between defective responses to DNA damage and cancer, and brings us closer to resolving the issue of cancer predisposition in some A-T carriers.
Journal ArticleDOI
Genomic instability — an evolving hallmark of cancer
TL;DR: The mutation patterns of the tumour suppressor TP53, ataxia telangiectasia mutated (ATM) and cyclin-dependent kinase inhibitor 2A (CDKN2A; which encodes p16INK4A and p14ARF) support the oncogene-induced DNA replication stress model, which attributes genomic instability and TP53 and ATM mutations to oncogen- induced DNA damage.
Journal ArticleDOI
An oncogene-induced DNA damage model for cancer development.
TL;DR: Oncogene-induced DNA damage may explain two key features of cancer: genomic instability and the high frequency of p53 mutations.