JEM_20091320.pdf (5.38 MB)
Histone H2AX stabilizes broken DNA strands to suppress chromosome breaks and translocations during V(D)J recombination
journal contribution
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 BassingThe 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
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Publication status
- Published
File Version
- Published version
Journal
Journal of Experimental MedicineISSN
0022-1007Publisher
Rockefeller University PressExternal DOI
Issue
12Volume
206Page range
2625-2639Department affiliated with
- Clinical and Experimental Medicine Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2013-02-11First Open Access (FOA) Date
2013-02-11First Compliant Deposit (FCD) Date
2013-02-11Usage metrics
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