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Gaggioli, V.* ; Lo, C.S.Y.* ; Reveron-Gomez, N.* ; Jasencakova, Z.* ; Domenech, H.* ; Nguyen, H.* ; Sidoli, S.* ; Tvardovskiy, A. ; Uruci, S.* ; Slotman, J.A.* ; Chai, Y.* ; Gonçalves, J.G.S.C.S.* ; Manolika, E.M.* ; Jensen, O.N.* ; Wheeler, D.* ; Sridharan, S.* ; Chakrabarty, S.* ; Demmers, J.* ; Kanaar, R.* ; Groth, A.* ; Taneja, N.*

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

Nat. Cell Biol. 25, 1017-1032 (2023)
DOI PMC
Creative Commons Lizenzvertrag
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Oncogene-induced Senescence; Dna-damage Response; S-phase Checkpoint; Histone H3; Chromatin-structure; Methyltransferase G9a; Lysine 36; In-vitro; Methylation; Stress
ISSN (print) / ISBN 1465-7392
e-ISSN 1476-4679
Journal Nature Cell Biology
Quellenangaben Volume: 25, Issue: 7, Pages: 1017-1032 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place Heidelberger Platz 3, Berlin, 14197, Germany
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Functional Epigenetics (IFE)
Grants European Research Council