HMCES protects immunoglobulin genes specifically from deletions during somatic hypermutation

Lizhen Wu, Vipul Shukla, Anurupa Devi Yadavalli, Ravi K. Dinesh, Dijin Xu, Anjana Rao, David G. Schatz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Somatic hypermutation (SHM) produces point mutations in immunoglobulin (Ig) genes in B cells when uracils created by the activation-induced deaminase are processed in a mutagenic manner by enzymes of the base excision repair (BER) and mismatch repair (MMR) pathways. Such uracil processing creates DNA strand breaks and is susceptible to the generation of deleterious deletions. Here, we demonstrate that the DNA repair factor HMCES strongly suppresses deletions without significantly affecting other parameters of SHM in mouse and human B cells, thereby facilitating the production of antigen-specific antibodies. The deletion-prone repair pathway suppressed by HMCES operates downstream from the uracil glycosylase UNG and is mediated by the combined action of BER factor APE2 and MMR factors MSH2, MSH6, and EXO1. HMCES's ability to shield against deletions during SHM requires its capacity to form covalent cross-links with abasic sites, in sharp contrast to its DNA end-joining role in class switch recombination but analogous to its genome-stabilizing role during DNA replication. Our findings lead to a novel model for the protection of Ig gene integrity during SHM in which abasic site cross-linking by HMCES intercedes at a critical juncture during processing of vulnerable gapped DNA intermediates by BER and MMR enzymes.

Original languageEnglish (US)
Pages (from-to)433-450
Number of pages18
JournalGenes and Development
Volume36
Issue number7
DOIs
StatePublished - Apr 1 2022

Funding

This work was funded by research funds from a Gruber Science Fellowship and a National Science Foundation Graduate Research Fellowship (to R.K.D.), Leukemia and Lymphoma Society grant 5463-18 (to V.S.), and National Institutes of Health grants R01 AI127642 (to D.G.S.), K99/R00 CA248835 (to V.S.), and R35 CA210043 (to A.R.).

Keywords

  • AID
  • HMCES
  • Somatic hypermutation
  • antibody affinity maturation
  • base excision repair
  • mismatch repair

ASJC Scopus subject areas

  • General Medicine

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