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. Epub 2019 Dec 2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / physiology*
  • Cell Line, Tumor
  • DNA / genetics*
  • DNA Breaks, Double-Stranded
  • DNA Damage / genetics
  • DNA End-Joining Repair / genetics*
  • DNA-Binding Proteins / genetics*
  • Immunoglobulin Class Switching / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Translocation, Genetic / genetics


  • DNA-Binding Proteins
  • Hmces protein, mouse
  • DNA