RAD51 protects human cells from transcription-replication conflicts.

Chromosomes / metabolism DNA Replication Humans Rad51 Recombinase / genetics S Phase / genetics Transcription, Genetic
common fragile sites gene amplification in cancer mitotic DNA synthesis oncogene-induced DNA replication stress replication fork protection

Journal

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

Informations de publication

Date de publication:
15 09 2022
Historique:
received: 08 02 2022
revised: 02 06 2022
accepted: 16 07 2022
pubmed: 25 8 2022
medline: 21 9 2022
entrez: 24 8 2022
Statut: ppublish

Résumé

Oncogene activation during tumorigenesis promotes DNA replication stress (RS), which subsequently drives the formation of cancer-associated chromosomal rearrangements. Many episodes of physiological RS likely arise due to conflicts between the DNA replication and transcription machineries operating simultaneously at the same loci. One role of the RAD51 recombinase in human cells is to protect replication forks undergoing RS. Here, we have identified a key role for RAD51 in preventing transcription-replication conflicts (TRCs) from triggering replication fork breakage. The genomic regions most affected by RAD51 deficiency are characterized by being replicated and transcribed in early S-phase and show significant overlap with loci prone to cancer-associated amplification. Consistent with a role for RAD51 in protecting against transcription-replication conflicts, many of the adverse effects of RAD51 depletion are ameliorated by inhibiting early S-phase transcription. We propose a model whereby RAD51 suppresses fork breakage and subsequent inadvertent amplification of genomic loci prone to experiencing TRCs.

Identifiants

DOI: 10.1016/j.molcel.2022.07.010 PMID: 36002000
pubmed: 36002000
pii: S1097-2765(22)00706-7
doi: 10.1016/j.molcel.2022.07.010
pii:
doi:

Substances chimiques

RAD51 protein, human EC 2.7.7.-
Rad51 Recombinase EC 2.7.7.-

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

3366-3381.e9

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2022 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors confirm that there are no relevant financial or nonfinancial competing interests to report.

Auteurs

Rahul Bhowmick (R)

Center for Chromosome Stability, Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.

Mads Lerdrup (M)

Center for Chromosome Stability, Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.

Sampath Amitash Gadi (SA)

Center for Chromosome Stability, Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.

Giacomo G Rossetti (GG)

Department of Molecular Biology, University of Geneva, 30, quai Ernest-Ansermet, 1205, Geneva, Switzerland.

Manika I Singh (MI)

Center for Chromosome Stability, Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.

Ying Liu (Y)

Center for Chromosome Stability, Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.

Thanos D Halazonetis (TD)

Department of Molecular Biology, University of Geneva, 30, quai Ernest-Ansermet, 1205, Geneva, Switzerland.

Ian D Hickson (ID)

Center for Chromosome Stability, Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark. Electronic address: iandh@sund.ku.dk.

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Classifications MeSH

questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Chromosomes › RAD51 protects human cells from...
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questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › RAD51 protects human cells from...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines des groupes de complémentation de l'anémie de Fanconi › Rad51 Recombinase › RAD51 protects human cells from...
questionsmedicales.fr › Phénomènes génétiques › Réplication de l'ADN › Phase S › RAD51 protects human cells from...
questionsmedicales.fr › Phénomènes génétiques › Expression des gènes › Transcription génétique › RAD51 protects human cells from...