2. Academic Validation
  3. HMCES Functions in the Alternative End-Joining Pathway of the DNA DSB Repair during Class Switch Recombination in B Cells

HMCES Functions in the Alternative End-Joining Pathway of the DNA DSB Repair during Class Switch Recombination in B Cells

  • Mol Cell. 2020 Jan 16;77(2):384-394.e4. doi: 10.1016/j.molcel.2019.10.031.
Vipul Shukla 1,  Levon Halabelian 2,  Sanjana Balagere 1,  Daniela Samaniego-Castruita 1,  Douglas E Feldman 3,  Cheryl H Arrowsmith 4,  Anjana Rao 5,  L Aravind 6
Affiliations

Affiliations

  • 1 Division of Signaling and Gene Expression, La Jolla Institute for Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
  • 2 Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • 3 Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles, CA 93033, USA.
  • 4 Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada. Electronic address: [email protected].
  • 5 Division of Signaling and Gene Expression, La Jolla Institute for Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA; Department of Pharmacology and Moores Cancer Center, University of San Diego, California, 9500 Gilman Drive, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA. Electronic address: [email protected].
  • 6 National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA. Electronic address: [email protected].
PMID: 31806351 DOI: 10.1016/j.molcel.2019.10.031
Abstract

HMCES (5hmC binding, embryonic stem cell-specific-protein), originally identified as a protein capable of binding 5-hydroxymethylcytosine (5hmC), an epigenetic modification generated by TET proteins, was previously reported to covalently crosslink to DNA at abasic sites via a conserved cysteine. We show here that Hmces-deficient mice display normal hematopoiesis without global alterations in 5hmC. HMCES specifically enables DNA double-strand break repair through the microhomology-mediated alternative-end-joining (Alt-EJ) pathway during class switch recombination (CSR) in B cells, and HMCES deficiency leads to a significant defect in CSR. HMCES mediates Alt-EJ through its SOS-response-associated-peptidase domain (SRAPd), a function that requires DNA binding but is independent of its autopeptidase and DNA-crosslinking activities. We show that HMCES is recruited to switch regions of the immunoglobulin locus and provide a potential structural basis for the interaction of HMCES with long DNA overhangs generated by Alt-EJ during CSR. Our studies provide further evidence for a specialized role for HMCES in DNA repair.

Keywords

DNA double-strand break (DNA DSB) repair; HMCES; TET proteins; alternative end joining; class switch recombination (CSR); oxidized methylcytosines.

Figures