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

Vipul Shukla, Levon Halabelian, Sanjana Balagere, Daniela Samaniego-Castruita, Douglas E. Feldman, Cheryl H. Arrowsmith*, Anjana Rao, L. Aravind

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)384-394.e4
JournalMolecular cell
Volume77
Issue number2
DOIs
StatePublished - Jan 16 2020

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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