Efficient Pre-mRNA Cleavage Prevents Replication-Stress-Associated Genome Instability.

Active Transport, Cell Nucleus Cell Cycle Proteins / genetics DNA Damage DNA Replication DNA, Neoplasm / genetics DNA-Binding Proteins Gene Expression Regulation, Neoplastic Genomic Instability HeLa Cells Humans Neoplasms / genetics Nuclear Proteins / genetics Nucleic Acid Heteroduplexes / genetics Polyadenylation RNA Cleavage RNA Precursors / biosynthesis RNA, Messenger / biosynthesis RNA, Neoplasm / biosynthesis RNA-Binding Proteins
ATR R-loops RNA:DNA hybrids checkpoint activation cleavage gene gating origin firing polyadenylation pre-mRNA processing replication catastrophe replication stress

Journal

Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571

Informations de publication

Date de publication:
21 02 2019
Historique:
received: 16 04 2018
revised: 31 08 2018
accepted: 28 11 2018
pubmed: 15 1 2019
medline: 25 6 2019
entrez: 15 1 2019
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.molcel.2018.11.036 PMID: 30639241 PMC: PMC6395949
pubmed: 30639241
pii: S1097-2765(18)31006-2
doi: 10.1016/j.molcel.2018.11.036
pmc: PMC6395949
pii:
doi:

Substances chimiques

Cell Cycle Proteins 0
DNA, Neoplasm 0
DNA-Binding Proteins 0
Nuclear Proteins 0
Nucleic Acid Heteroduplexes 0
RNA Precursors 0
RNA, Messenger 0
RNA, Neoplasm 0
RNA-Binding Proteins 0
THOC1 protein, human 0
WDR33 protein, human 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

670-683.e12

Subventions

Organisme : European Research Council
ID : 714326
Pays : International

Informations de copyright

Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

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Auteurs

Federico Teloni (F)

Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland; Life Science Zurich Graduate School (LSZGS), 8057 Zurich, Switzerland.

Jone Michelena (J)

Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland.

Aleksandra Lezaja (A)

Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland; Life Science Zurich Graduate School (LSZGS), 8057 Zurich, Switzerland.

Sinan Kilic (S)

Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland.

Christina Ambrosi (C)

Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland; Life Science Zurich Graduate School (LSZGS), 8057 Zurich, Switzerland.

Shruti Menon (S)

Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland; Life Science Zurich Graduate School (LSZGS), 8057 Zurich, Switzerland.

Jana Dobrovolna (J)

Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, 143 00 Czech Republic.

Ralph Imhof (R)

Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland.

Pavel Janscak (P)

Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland; Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, 143 00 Czech Republic.

Tuncay Baubec (T)

Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland.

Matthias Altmeyer (M)

Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland. Electronic address: matthias.altmeyer@uzh.ch.

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Classifications MeSH

Recherchemedicale.com › Métabolisme › Transport biologique › Transport des protéines › Transport nucléaire actif › Efficient Pre-mRNA Cleavage Prevents...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines du cycle cellulaire › Efficient Pre-mRNA Cleavage Prevents...
Recherchemedicale.com › Phénomènes génétiques › Altération de l'ADN › Efficient Pre-mRNA Cleavage Prevents...
Recherchemedicale.com › Phénomènes génétiques › Réplication de l'ADN › Efficient Pre-mRNA Cleavage Prevents...
Recherchemedicale.com › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ADN › ADN tumoral › Efficient Pre-mRNA Cleavage Prevents...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines de liaison à l'ADN › Efficient Pre-mRNA Cleavage Prevents...
Recherchemedicale.com › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › Efficient Pre-mRNA Cleavage Prevents...
Recherchemedicale.com › Phénomènes génétiques › Instabilité du génome › Efficient Pre-mRNA Cleavage Prevents...
Recherchemedicale.com › Cellules › Cellules épithéliales › Cellules HeLa › Efficient Pre-mRNA Cleavage Prevents...
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Recherchemedicale.com › Tumeurs › Efficient Pre-mRNA Cleavage Prevents...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines nucléaires › Efficient Pre-mRNA Cleavage Prevents...
Recherchemedicale.com › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › Hétéroduplexes d'acides nucléiques › Efficient Pre-mRNA Cleavage Prevents...
Recherchemedicale.com › Phénomènes génétiques › Régulation de l'expression des gènes › Maturation post-transcriptionnelle des ARN › Maturation de l'extrémité 3' des ARN › Polyadénylation › Efficient Pre-mRNA Cleavage Prevents...
Recherchemedicale.com › Phénomènes génétiques › Clivage de l'ARN › Efficient Pre-mRNA Cleavage Prevents...
Recherchemedicale.com › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › Précurseurs des ARN › Efficient Pre-mRNA Cleavage Prevents...
Recherchemedicale.com › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN messager › Efficient Pre-mRNA Cleavage Prevents...
Recherchemedicale.com › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN tumoral › Efficient Pre-mRNA Cleavage Prevents...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Protéines de liaison à l'ARN › Efficient Pre-mRNA Cleavage Prevents...