SETD2-Dependent Histone H3K36 Trimethylation Is Required for Homologous Recombination Repair and Genome Stability
Sophia X. Pfister,
Sara Ahrabi,
Lykourgos-Panagiotis Zalmas,
Sovan Sarkar,
François Aymard,
Csanád Z. Bachrati,
Thomas Helleday,
Gaëlle Legube,
Nicholas B. La Thangue,
Andrew C.G. Porter,
Timothy C. Humphrey
Affiliations
Sophia X. Pfister
CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK
Sara Ahrabi
CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK
Lykourgos-Panagiotis Zalmas
Laboratory of Cancer Biology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK
Sovan Sarkar
CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK
François Aymard
Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, Université de Toulouse, Université Paul Sabatier, 31062 Toulouse, France
Csanád Z. Bachrati
School of Life Sciences, University of Lincoln, Lincoln LN6 7TS, UK
Thomas Helleday
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 21 Stockholm, Sweden
Gaëlle Legube
Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, Université de Toulouse, Université Paul Sabatier, 31062 Toulouse, France
Nicholas B. La Thangue
Laboratory of Cancer Biology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK
Andrew C.G. Porter
Gene Targeting Group, Centre for Haematology, Imperial College Faculty of Medicine, London W12 0NN, UK
Timothy C. Humphrey
CRUK MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK
Modulating chromatin through histone methylation orchestrates numerous cellular processes. SETD2-dependent trimethylation of histone H3K36 is associated with active transcription. Here, we define a role for H3K36 trimethylation in homologous recombination (HR) repair in human cells. We find that depleting SETD2 generates a mutation signature resembling RAD51 depletion at I-SceI-induced DNA double-strand break (DSB) sites, with significantly increased deletions arising through microhomology-mediated end-joining. We establish a presynaptic role for SETD2 methyltransferase in HR, where it facilitates the recruitment of C-terminal binding protein interacting protein (CtIP) and promotes DSB resection, allowing Replication Protein A (RPA) and RAD51 binding to DNA damage sites. Furthermore, reducing H3K36me3 levels by overexpressing KDM4A/JMJD2A, an oncogene and H3K36me3/2 demethylase, or an H3.3K36M transgene also reduces HR repair events. We propose that error-free HR repair within H3K36me3-decorated transcriptionally active genomic regions promotes cell homeostasis. Moreover, these findings provide insights as to why oncogenic mutations cluster within the H3K36me3 axis.
