@article{eca18b7ecdf740c99fbd529e4ddf81e7,
title = "Genome-wide Identification of Structure-Forming Repeats as Principal Sites of Fork Collapse upon ATR Inhibition",
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. Shastri et al. have identified new classes of difficult-to-replicate sequences in the mouse and human genomes that are highly dependent on ATR function for stability during DNA replication. Structure-forming short tandem repeats, inverted retroelements, and quasi-palindromic AT-rich repeats characterize the sites for fork collapse caused by ATR inhibition.",
author = "Nishita Shastri and Tsai, {Yu Chen} and Suzanne Hile and Deondre Jordan and Barrett Powell and Jessica Chen and Dillon Maloney and Marei Dose and Yancy Lo and Theonie Anastassiadis and Osvaldo Rivera and Taehyong Kim and Sharvin Shah and Piyush Borole and Kanika Asija and Xiang Wang and Smith, {Kevin D.} and Darren Finn and Jonathan Schug and Rafael Casellas and Yatsunyk, {Liliya A.} and Eckert, {Kristin A.} and Brown, {Eric J.}",
note = "Funding Information: This project was funded by grants from the NIH (E.J.B.: 2R01AG027376 and 1R01CA189743; N.S.: 5R25CA101871; Y.-C.T: T32ES019851; L.A.Y.: 1R15CA208676). Additional funding was provided through the Pennsylvania Department of Health (E.J.B.), Center of Excellence in Environmental Toxicology (P30ES013508, E.J.B.), Basser Center for BRCA Research (E.J.B.), Abramson Family Cancer Research Institute (E.J.B.), Camille and Henry Dreyfus Teacher-Scholar Award (L.A.Y.), and Jake Gittlen Cancer Research Foundation (K.A.E.). We are grateful to Dr. Jean-Louis Mergny (IECB, Bordeaux, France), in whose laboratory some of these studies were conducted (L.A.Y.). We would also like to thank Dr. J. Brad Chaires for CD/TDS principal-component comparisons to existing signatures and Dr. Beverly Emanuel (CHOP) for helpful insights. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Funding Information: This project was funded by grants from the NIH (E.J.B.: 2R01AG027376 and 1R01CA189743 ; N.S.: 5R25CA101871 ; Y.-C.T: T32ES019851 ; L.A.Y.: 1R15CA208676 ). Additional funding was provided through the Pennsylvania Department of Health (E.J.B.), Center of Excellence in Environmental Toxicology ( P30ES013508 , E.J.B.), Basser Center for BRCA Research (E.J.B.), Abramson Family Cancer Research Institute (E.J.B.), Camille and Henry Dreyfus Teacher-Scholar Award (L.A.Y.), and Jake Gittlen Cancer Research Foundation (K.A.E.). We are grateful to Dr. Jean-Louis Mergny (IECB, Bordeaux, France), in whose laboratory some of these studies were conducted (L.A.Y.). We would also like to thank Dr. J. Brad Chaires for CD/TDS principal-component comparisons to existing signatures and Dr. Beverly Emanuel (CHOP) for helpful insights. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = oct,
day = "18",
doi = "10.1016/j.molcel.2018.08.047",
language = "English (US)",
volume = "72",
pages = "222--238.e11",
journal = "Molecular cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "2",
}