DNA damage sensing by the ATM and ATR kinases.
Alexandre Maréchal,Lee Zou +1 more
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TLDR
The recent findings and current models of how ATM and ATR senseDNA damage, how they are activated by DNA damage, and how they function in concert to regulate the DDR are discussed.Abstract:
In eukaryotic cells, maintenance of genomic stability relies on the coordinated action of a network of cellular processes, including DNA replication, DNA repair, cell-cycle progression, and others. The DNA damage response (DDR) signaling pathway orchestrated by the ATM and ATR kinases is the central regulator of this network in response to DNA damage. Both ATM and ATR are activated by DNA damage and DNA replication stress, but their DNA-damage specificities are distinct and their functions are not redundant. Furthermore, ATM and ATR often work together to signal DNA damage and regulate downstream processes. Here, we will discuss the recent findings and current models of how ATM and ATR sense DNA damage, how they are activated by DNA damage, and how they function in concert to regulate the DDR.read more
Citations
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YU238259 Is a Novel Inhibitor of Homology-Dependent DNA Repair That Exhibits Synthetic Lethality and Radiosensitization in Repair-Deficient Tumors
Gregory C. Stachelek,Elizabeth Peterson-Roth,Yanfeng Liu,Rafael J. Fernandez,Luke R.G. Pike,Jack M. Qian,Laura Abriola,Denton Hoyer,William Hungerford,Janie Merkel,Peter M. Glazer +10 more
TL;DR: It is demonstrated that YU238259, a member of a novel class of DNA double-strand break repair inhibitors, exhibits potent synthetic lethality in the setting of DNA damage response and DNA repair defects, and suggests that it may have clinical benefit to patients with advanced BRCA2-negative tumors.
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RADX interacts with single-stranded DNA to promote replication fork stability.
TL;DR: Deregulation of RADX expression and ssDNA binding leads to enhanced replication fork stalling and degradation, and this work provides evidence that a balanced interplay between RADX and RPA ssDNA‐binding activities is critical for avoiding these defects.
Journal ArticleDOI
Role of RUNX Family Transcription Factors in DNA Damage Response.
TL;DR: The functional role and mechanisms involved in RUNX factor mediated response to DNA damage and other cellular stresses are discussed and the impact of these new findings on understanding of cancer predisposition associated with RunX factor dysregulation is highlighted.
Journal ArticleDOI
SERPINE2/PN-1 regulates the DNA damage response and radioresistance by activating ATM in lung cancer.
Jingjing Zhang,Jingjing Zhang,Qiong Wu,Lucheng Zhu,Shu-jun Xie,Shu-jun Xie,Linglan Tu,Yuhong Yang,Kan Wu,Yan-yan Zhao,Yan-yan Zhao,Yuqing Wang,Yuqing Wang,Yasi Xu,Yasi Xu,Xueqin Chen,Shenglin Ma,Shirong Zhang +17 more
TL;DR: In this article, the serine proteinase inhibitor clade E member 2 (SERPINE2) was identified as a modulator of radiosensitivity and the DNA damage response (DDR) in lung cancer.
Journal ArticleDOI
Cell cycle checkpoint control in response to DNA damage by environmental stresses.
TL;DR: The DNA damage response (DDR) pathway as discussed by the authors is composed of both highly conserved and plant-specific elements to cope with biotic and abiotic stresses, including metal toxicity, cold, salinity, and phosphate deficiency.
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
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
TL;DR: It is shown that ATM is held inactive in unirradiated cells as a dimer or higher-order multimer, with the kinase domain bound to a region surrounding serine 1981 that is contained within the previously described ‘FAT’ domain.
Journal ArticleDOI
The DNA damage response: putting checkpoints in perspective
TL;DR: The inability to repair DNA damage properly in mammals leads to various disorders and enhanced rates of tumour development, and this work has shown that direct activation of DNA repair networks is needed to correct this problem.
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
Sensing DNA Damage Through ATRIP Recognition of RPA-ssDNA Complexes
Lee Zou,Stephen J. Elledge +1 more
TL;DR: The data suggest that RPA-coated ssDNA is the critical structure at sites of DNA damage that recruits the ATR-ATRIP complex and facilitates its recognition of substrates for phosphorylation and the initiation of checkpoint signaling.
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