Dynamic de novo heterochromatin assembly and disassembly at replication forks ensures fork stability.

Humans Histones / genetics Heterochromatin / genetics Chromatin / genetics Chromatin Assembly and Disassembly DNA Replication Histocompatibility Antigens Histone-Lysine N-Methyltransferase / genetics Jumonji Domain-Containing Histone Demethylases / genetics

Journal

Nature cell biology

ISSN: 1476-4679

Titre abrégé: Nat Cell Biol

Pays: England

ID NLM: 100890575

Informations de publication

Date de publication:
Jul 2023

Historique:

received: 11 11 2022

accepted: 16 05 2023

medline: 17 7 2023

pubmed: 7 7 2023

entrez: 6 7 2023

Statut: ppublish

Résumé

Chromatin is dynamically reorganized when DNA replication forks are challenged. However, the process of epigenetic reorganization and its implication for fork stability is poorly understood. Here we discover a checkpoint-regulated cascade of chromatin signalling that activates the histone methyltransferase EHMT2/G9a to catalyse heterochromatin assembly at stressed replication forks. Using biochemical and single molecule chromatin fibre approaches, we show that G9a together with SUV39h1 induces chromatin compaction by accumulating the repressive modifications, H3K9me1/me2/me3, in the vicinity of stressed replication forks. This closed conformation is also favoured by the G9a-dependent exclusion of the H3K9-demethylase JMJD1A/KDM3A, which facilitates heterochromatin disassembly upon fork restart. Untimely heterochromatin disassembly from stressed forks by KDM3A enables PRIMPOL access, triggering single-stranded DNA gap formation and sensitizing cells towards chemotherapeutic drugs. These findings may help in explaining chemotherapy resistance and poor prognosis observed in patients with cancer displaying elevated levels of G9a/H3K9me3.

Identifiants

DOI: 10.1038/s41556-023-01167-z PMID: 37414849 PMC: PMC10344782

pubmed: 37414849

doi: 10.1038/s41556-023-01167-z

pii: 10.1038/s41556-023-01167-z

pmc: PMC10344782

doi:

Substances chimiques

Histones 0

Heterochromatin 0

Chromatin 0

EHMT2 protein, human EC 2.1.1.43

Histocompatibility Antigens 0

Histone-Lysine N-Methyltransferase EC 2.1.1.43

KDM3A protein, human EC 1.14.11.-

Jumonji Domain-Containing Histone Demethylases EC 1.14.11.-

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

1017-1032

Subventions

Organisme : European Research Council

ID : 101078750

Pays : International

Informations de copyright

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