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

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

  • Nat Cell Biol. 2023 Jul 6. doi: 10.1038/s41556-023-01167-z.
Vincent Gaggioli # 1 2,  Calvin S Y Lo # 1,  Nazaret Reverón-Gómez 3 4,  Zuzana Jasencakova 3 4,  Heura Domenech 1,  Hong Nguyen 1,  Simone Sidoli 5 6,  Andrey Tvardovskiy 5 7,  Sidrit Uruci 1,  Johan A Slotman 8,  Yi Chai 9,  João G S C Souto Gonçalves 10,  Eleni Maria Manolika 1,  Ole N Jensen 5,  David Wheeler 11,  Sriram Sridharan 9,  Sanjiban Chakrabarty 12,  Jeroen Demmers 13,  Roland Kanaar 1 2,  Anja Groth 3 4,  Nitika Taneja 14
Affiliations

Affiliations

  • 1 Department of Molecular Genetics, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
  • 2 Oncode Institute, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
  • 3 Novo Nordisk Foundation Center for Protein Research (CPR), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 4 Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 5 Department of Biochemistry & Molecular Biology, VILLUM Centre for Bioanalytical Sciences and Centre for Epigenetics, University of Southern Denmark, Odense, Denmark.
  • 6 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 7 Institute of Functional Epigenetics (IFE), Helmholtz Zentrum Munchen, Neuherberg, Germany.
  • 8 Department of Pathology, Erasmus Optical Imaging Centre, Erasmus Medical Center, Rotterdam, the Netherlands.
  • 9 Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore.
  • 10 Department of Molecular Genetics, King's College London, London, UK.
  • 11 Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 12 Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India.
  • 13 Proteomics Center and Department of Biochemistry, Erasmus University Medical Centre, Rotterdam, the Netherlands.
  • 14 Department of Molecular Genetics, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands. n.taneja@erasmusmc.nl.
  • # Contributed equally.
PMID: 37414849 DOI: 10.1038/s41556-023-01167-z
Abstract

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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