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Publication Detail

Title: Genome-wide Identification of Structure-Forming Repeats as Principal Sites of Fork Collapse upon ATR Inhibition.

Authors: Shastri, Nishita; Tsai, Yu-Chen; Hile, Suzanne; Jordan, Deondre; Powell, Barrett; Chen, Jessica; Maloney, Dillon; Dose, Marei; Lo, Yancy; Anastassiadis, Theonie; Rivera, Osvaldo; Kim, Taehyong; Shah, Sharvin; Borole, Piyush; Asija, Kanika; Wang, Xiang; Smith, Kevin D; Finn, Darren; Schug, Jonathan; Casellas, Rafael; Yatsunyk, Liliya A; Eckert, Kristin A; Brown, Eric J

Published In Mol Cell, (2018 10 18)

Abstract: DNA polymerase stalling activates the ATR checkpoint kinase, which in turn suppresses fork collapse and breakage. Herein, we describe use of ATR inhibition (ATRi) as a means to identify genomic sites of problematic DNA replication in murine and human cells. Over 500 high-resolution ATR-dependent sites were ascertained using two distinct methods: replication protein A (RPA)-chromatin immunoprecipitation (ChIP) and breaks identified by TdT labeling (BrITL). The genomic feature most strongly associated with ATR dependence was repetitive DNA that exhibited high structure-forming potential. Repeats most reliant on ATR for stability included structure-forming microsatellites, inverted retroelement repeats, and quasi-palindromic AT-rich repeats. Notably, these distinct categories of repeats differed in the structures they formed and their ability to stimulate RPA accumulation and breakage, implying that the causes and character of replication fork collapse under ATR inhibition can vary in a DNA-structure-specific manner. Collectively, these studies identify key sources of endogenous replication stress that rely on ATR for stability.

PubMed ID: 30293786 Exiting the NIEHS site

MeSH Terms: Animals; Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors*; Ataxia Telangiectasia Mutated Proteins/genetics*; Cell Cycle Proteins/genetics; Chromatin Immunoprecipitation/methods; Chromatin/genetics; DNA Breaks, Double-Stranded; DNA Damage/genetics; DNA Replication/genetics*; Female; Genomic Instability/genetics; Humans; Mice; Microsatellite Repeats/genetics*; Replication Protein A/genetics

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