title: A histone H3K36 chromatin switch coordinates DNA double-strand break repair pathway choice.
abstract: DNA double-strand break (DSB) repair is a highly regulated process performed predominantly by non-homologous end joining (NHEJ) or homologous recombination (HR) pathways. How these pathways are coordinated in the context of chromatin is unclear. Here we uncover a role for histone H3K36 modification in regulating DSB repair pathway choice in fission yeast. We find Set2-dependent H3K36 methylation reduces chromatin accessibility, reduces resection and promotes NHEJ, while antagonistic Gcn5-dependent H3K36 acetylation increases chromatin accessibility, increases resection and promotes HR. Accordingly, loss of Set2 increases H3K36Ac, chromatin accessibility and resection, while Gcn5 loss results in the opposite phenotypes following DSB induction. Further, H3K36 modification is cell cycle regulated with Set2-dependent H3K36 methylation peaking in G1 when NHEJ occurs, while Gcn5-dependent H3K36 acetylation peaks in S/G2 when HR prevails. These findings support an H3K36 chromatin switch in regulating DSB repair pathway choice.
authors.affiliation: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, ORCRB, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Chen-Chun
authors.initials: CC
authors.lastname: Pai
authors.affiliation: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, ORCRB, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Deegan
authors.affiliation: Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, The University of Edinburgh, Swann Building, Mayfield Road, Edinburgh EH9 3JR, UK.
authors.forename: Lakxmi
authors.initials: L
authors.lastname: Subramanian
authors.affiliation: Institute for Cell and Molecular Biosciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Csenge
authors.initials: C
authors.lastname: Gal
authors.affiliation: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, ORCRB, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Sovan
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, ORCRB, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Blaikley
authors.affiliation: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, ORCRB, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Carol
authors.initials: C
authors.lastname: Walker
authors.affiliation: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, ORCRB, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Lydia
authors.initials: L
authors.lastname: Hulme
authors.affiliation: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, ORCRB, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Eric
authors.initials: E
authors.lastname: Bernhard
authors.affiliation: University College London, Department of Genetics, Evolution and Environment, Darwin Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Sandra
authors.initials: S
authors.lastname: Codlin
authors.affiliation: University College London, Department of Genetics, Evolution and Environment, Darwin Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Jürg
authors.initials: J
authors.lastname: Bähler
authors.affiliation: Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, The University of Edinburgh, Swann Building, Mayfield Road, Edinburgh EH9 3JR, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Allshire
authors.affiliation: Institute for Cell and Molecular Biosciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Whitehall
authors.affiliation: CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, ORCRB, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Humphrey
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism*; D059766:DNA End-Joining Repair; D004260:DNA Repair; D004271:DNA, Fungal / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D008745:Methylation; D059767:Recombinational DNA Repair; D012568:Schizosaccharomyces / Q000235:genetics* / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D000123:Acetyltransferases; D002843:Chromatin; D004271:DNA, Fungal; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D029702:Schizosaccharomyces pombe Proteins; C527202:Set2 protein, S pombe; C501322:Gcn5 protein, S pombe; D000099224:p300-CBP-Associated Factor