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Efficient pre-mRNA cleavage prevents replication-stress-associated genome instability


Teloni, Federico; Michelena, Jone; Lezaja, Aleksandra; Kilic, Sinan; Ambrosi, Christina; Menon, Shruti; Dobrovolna, Jana; Imhof, Ralph; Janscak, Pavel; Baubec, Tuncay; Altmeyer, Matthias (2019). Efficient pre-mRNA cleavage prevents replication-stress-associated genome instability. Molecular Cell, 73(4):670-683.e12.

Abstract

Cellular mechanisms that safeguard genome integrity are often subverted in cancer. To identify cancer-related genome caretakers, we employed a convergent multi-screening strategy coupled to quantitative image-based cytometry and ranked candidate genes according to multivariate readouts reflecting viability, proliferative capacity, replisome integrity, and DNA damage signaling. This unveiled regulators of replication stress resilience, including components of the pre-mRNA cleavage and polyadenylation complex. We show that deregulation of pre-mRNA cleavage impairs replication fork speed and leads to excessive origin activity, rendering cells highly dependent on ATR function. While excessive formation of RNA:DNA hybrids under these conditions was tightly associated with replication-stress-induced DNA damage, inhibition of transcription rescued fork speed, origin activation, and alleviated replication catastrophe. Uncoupling of pre-mRNA cleavage from co-transcriptional processing and export also protected cells from replication-stress-associated DNA damage, suggesting that pre-mRNA cleavage provides a mechanism to efficiently release nascent transcripts and thereby prevent gene gating-associated genomic instability.

Abstract

Cellular mechanisms that safeguard genome integrity are often subverted in cancer. To identify cancer-related genome caretakers, we employed a convergent multi-screening strategy coupled to quantitative image-based cytometry and ranked candidate genes according to multivariate readouts reflecting viability, proliferative capacity, replisome integrity, and DNA damage signaling. This unveiled regulators of replication stress resilience, including components of the pre-mRNA cleavage and polyadenylation complex. We show that deregulation of pre-mRNA cleavage impairs replication fork speed and leads to excessive origin activity, rendering cells highly dependent on ATR function. While excessive formation of RNA:DNA hybrids under these conditions was tightly associated with replication-stress-induced DNA damage, inhibition of transcription rescued fork speed, origin activation, and alleviated replication catastrophe. Uncoupling of pre-mRNA cleavage from co-transcriptional processing and export also protected cells from replication-stress-associated DNA damage, suggesting that pre-mRNA cleavage provides a mechanism to efficiently release nascent transcripts and thereby prevent gene gating-associated genomic instability.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Department of Molecular Mechanisms of Disease
07 Faculty of Science > Department of Molecular Mechanisms of Disease
Dewey Decimal Classification:570 Life sciences; biology
Uncontrolled Keywords:Cell Biology, Molecular Biology, ATR; R-loops; RNA:DNA hybrids; checkpoint activation; cleavage; gene gating; origin firing; polyadenylation; pre-mRNA processing; replication catastrophe; replication stress
Language:English
Date:1 February 2019
Deposited On:18 Feb 2019 17:19
Last Modified:01 Apr 2019 11:03
Publisher:Cell Press (Elsevier)
ISSN:1097-2765
OA Status:Green
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.molcel.2018.11.036
PubMed ID:30639241
Project Information:
  • : FunderSNSF
  • : Grant IDPP00P3_179057
  • : Project TitleUncovering concealed regulators and unexpected pathway connections guarding against genome instability
  • : FunderSNSF
  • : Grant IDPP00P3_150690
  • : Project TitleUncovering concealed regulators and unexpected pathway connections guarding against genome instability
  • : FunderH2020
  • : Grant ID714326
  • : Project TitleDiVineGenoMe - Decoding cell-to-cell variation in genome integrity maintenance
  • : FunderSNSF
  • : Grant IDPP00P3_157488
  • : Project TitleEpigenomic patterns: generation, interpretation and their role in regulating genome function
  • : FunderSNSF
  • : Grant ID31003A_166451
  • : Project TitleExploring the molecular mechanisms of genome stability maintenance during DNA replication stress
  • : FunderSNSF
  • : Grant IDCRSII5_180345
  • : Project TitleChemical modulation of bromodomain function in development and disease
  • : FunderSNSF
  • : Grant IDPP00P3_157488
  • : Project TitleEpigenomic patterns: generation, interpretation and their role in regulating genome function
  • : FunderSNSF
  • : Grant ID31003A_166451
  • : Project TitleExploring the molecular mechanisms of genome stability maintenance during DNA replication stress
  • : FunderSNSF
  • : Grant IDCRSII5_180345
  • : Project TitleChemical modulation of bromodomain function in development and disease

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