ATM pathway activation limits R-loop-associated genomic instability in Werner syndrome cells.


Journal

Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011

Informations de publication

Date de publication:
23 04 2019
Historique:
accepted: 11 01 2019
revised: 08 01 2019
received: 12 07 2018
pubmed: 19 1 2019
medline: 11 10 2019
entrez: 19 1 2019
Statut: ppublish

Résumé

Werner syndrome (WS) is a cancer-prone disease caused by deficiency of Werner protein (WRN). WRN maintains genome integrity by promoting replication-fork stability after various forms of replication stress. Under mild replication stress, WS cells show impaired ATR-mediated CHK1 activation. However, it remains unclear if WS cells elicit other repair pathway. We demonstrate that loss of WRN leads to enhanced ATM phosphorylation upon prolonged exposure to aphidicolin, a specific inhibitor of DNA polymerases, resulting in CHK1 activation. Moreover, we find that loss of WRN sensitises cells to replication-transcription collisions and promotes accumulation of R-loops, which undergo XPG-dependent cleavage responsible for ATM signalling activation. Importantly, we observe that ATM pathway limits chromosomal instability in WS cells. Finally, we prove that, in WS cells, genomic instability enhanced upon chemical inhibition of ATM kinase activity is counteracted by direct or indirect suppression of R-loop formation or by XPG abrogation. Together, these findings suggest a potential role of WRN as regulator of R-loop-associated genomic instability, strengthening the notion that conflicts between replication and transcription can affect DNA replication, leading to human disease and cancer.

Identifiants

pubmed: 30657978
pii: 5290491
doi: 10.1093/nar/gkz025
pmc: PMC6468170
doi:

Substances chimiques

Aphidicolin 38966-21-1
ATM protein, human EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins EC 2.7.11.1
CHEK1 protein, human EC 2.7.11.1
Checkpoint Kinase 1 EC 2.7.11.1
WRN protein, human EC 3.6.4.12
Werner Syndrome Helicase EC 3.6.4.12

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

3485-3502

Informations de copyright

© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.

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Auteurs

Veronica Marabitti (V)

Department of Environment and Health, Section of Mechanisms Biomarkers and Models, Istituto Superiore di Sanita', Viale Regina Elena 299, Rome 00161, Italy.

Giorgia Lillo (G)

Department of Environment and Health, Section of Mechanisms Biomarkers and Models, Istituto Superiore di Sanita', Viale Regina Elena 299, Rome 00161, Italy.

Eva Malacaria (E)

Department of Environment and Health, Section of Mechanisms Biomarkers and Models, Istituto Superiore di Sanita', Viale Regina Elena 299, Rome 00161, Italy.

Valentina Palermo (V)

Department of Environment and Health, Section of Mechanisms Biomarkers and Models, Istituto Superiore di Sanita', Viale Regina Elena 299, Rome 00161, Italy.

Massimo Sanchez (M)

Department of Cell Biology and Neurosciences, Section of Gene and Cell Therapy, Istituto Superiore di Sanita', Viale Regina Elena 299, Rome 00161, Italy.

Pietro Pichierri (P)

Department of Environment and Health, Section of Mechanisms Biomarkers and Models, Istituto Superiore di Sanita', Viale Regina Elena 299, Rome 00161, Italy.

Annapaola Franchitto (A)

Department of Environment and Health, Section of Mechanisms Biomarkers and Models, Istituto Superiore di Sanita', Viale Regina Elena 299, Rome 00161, Italy.

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