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

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posted on 2023-06-08, 14:17 authored by 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
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 Igkappa 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-alpha/delta 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

History

Publication status

  • Published

File Version

  • Published version

Journal

Journal of Experimental Medicine

ISSN

0022-1007

Publisher

Rockefeller University Press

Issue

12

Volume

206

Page range

2625-2639

Department affiliated with

  • Clinical and Experimental Medicine Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2013-02-11

First Open Access (FOA) Date

2013-02-11

First Compliant Deposit (FCD) Date

2013-02-11

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