Histone H2AX stabilizes broken DNA strands to suppress chromosome breaks and translocations during V(D)J recombination

Bu Yin, Velibor Savic, Marisa M. Juntilla, Andrea L. Bredemeyer, Katherine S. Yang-Iott, Beth A. Helmink, Gary A. Koretzky, Barry P. Sleckman, Craig H. Bassing

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

The H2AX core histone variant is phosphorylated in chromatin around DNA double strand breaks (DSBs) and functions through unknown mechanisms to suppress antigen receptor locus translocations during V(D)J recombination. Formation of chromosomal coding joins and suppression of translocations involves the ataxia telangiectasia mutated and DNA-dependent protein kinase catalytic subunit serine/threonine kinases, each of which phosphorylates H2AX along cleaved antigen receptor loci. Using Abelson transformed pre-B cell lines, we find that H2AX is not required for coding join formation within chromosomal V(D)J recombination substrates. Yet we show that H2AX is phosphorylated along cleaved Igκ DNA strands and prevents their separation in G1 phase cells and their progression into chromosome breaks and translocations after cellular proliferation. We also show that H2AX prevents chromosome breaks emanating from unrepaired RAG endonuclease-generated TCR-α/δ locus coding ends in primary thymocytes. Our data indicate that histone H2AX suppresses translocations during V(D)J recombination by creating chromatin modifications that stabilize disrupted antigen receptor locus DNA strands to prevent their irreversible dissociation. We propose that such H2AX-dependent mechanisms could function at additional chromosomal locations to facilitate the joining of DNA ends generated by other types of DSBs.

Original languageEnglish (US)
Pages (from-to)2625-2639
Number of pages15
JournalJournal of Experimental Medicine
Volume206
Issue number12
DOIs
StatePublished - Nov 23 2009
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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