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

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

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)222-238.e11
JournalMolecular cell
Volume72
Issue number2
DOIs
StatePublished - Oct 18 2018

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Replication Protein A
Retroelements
DNA Replication
Microsatellite Repeats
Genome
Chromatin Immunoprecipitation
DNA
Human Genome
DNA-Directed DNA Polymerase
Phosphotransferases

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Shastri, N., Tsai, Y. C., Hile, S., Jordan, D., Powell, B., Chen, J., ... Brown, E. J. (2018). Genome-wide Identification of Structure-Forming Repeats as Principal Sites of Fork Collapse upon ATR Inhibition. Molecular cell, 72(2), 222-238.e11. https://doi.org/10.1016/j.molcel.2018.08.047
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 ; Brown, Eric J. / Genome-wide Identification of Structure-Forming Repeats as Principal Sites of Fork Collapse upon ATR Inhibition. In: Molecular cell. 2018 ; Vol. 72, No. 2. pp. 222-238.e11.
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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.",
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Shastri, N, Tsai, YC, Hile, S, Jordan, D, Powell, B, Chen, J, Maloney, D, Dose, M, Lo, Y, Anastassiadis, T, Rivera, O, Kim, T, Shah, S, Borole, P, Asija, K, Wang, X, Smith, KD, Finn, D, Schug, J, Casellas, R, Yatsunyk, LA, Eckert, K & Brown, EJ 2018, 'Genome-wide Identification of Structure-Forming Repeats as Principal Sites of Fork Collapse upon ATR Inhibition', Molecular cell, vol. 72, no. 2, pp. 222-238.e11. https://doi.org/10.1016/j.molcel.2018.08.047

Genome-wide Identification of Structure-Forming Repeats as Principal Sites of Fork Collapse upon ATR Inhibition. / 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; Brown, Eric J.

In: Molecular cell, Vol. 72, No. 2, 18.10.2018, p. 222-238.e11.

Research output: Contribution to journalArticle

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T1 - Genome-wide Identification of Structure-Forming Repeats as Principal Sites of Fork Collapse upon ATR Inhibition

AU - Shastri, Nishita

AU - Tsai, Yu Chen

AU - Hile, Suzanne

AU - Jordan, Deondre

AU - Powell, Barrett

AU - Chen, Jessica

AU - Maloney, Dillon

AU - Dose, Marei

AU - Lo, Yancy

AU - Anastassiadis, Theonie

AU - Rivera, Osvaldo

AU - Kim, Taehyong

AU - Shah, Sharvin

AU - Borole, Piyush

AU - Asija, Kanika

AU - Wang, Xiang

AU - Smith, Kevin D.

AU - Finn, Darren

AU - Schug, Jonathan

AU - Casellas, Rafael

AU - Yatsunyk, Liliya A.

AU - Eckert, Kristin

AU - Brown, Eric J.

PY - 2018/10/18

Y1 - 2018/10/18

N2 - 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.

AB - 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.

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