Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors.

Abstract:

:We employed gene targeting to study H2AX, a histone variant phosphorylated in chromatin surrounding DNA double-strand breaks. Mice deficient for both H2AX and p53 (H(delta/delta)P(-/-)) rapidly developed immature T and B lymphomas and solid tumors. Moreover, H2AX haploinsufficiency caused genomic instability in normal cells and, on a p53-deficient background, early onset of various tumors including more mature B lymphomas. Most H2AX(delta/delta)p53(-/-) or H2AX(+/delta)p53(-/-) B lineage lymphomas harbored chromosome 12 (IgH)/15 (c-myc) translocations with hallmarks of either aberrant V(D)J or class switch recombination. In contrast, H2AX(delta/delta)p53(-/-) thymic lymphomas had clonal translocations that did not involve antigen receptor loci and which likely occurred during cellular expansion. Thus, H2AX helps prevent aberrant repair of both programmed and general DNA breakage and, thereby, functions as a dosage-dependent suppressor of genomic instability and tumors in mice. Notably, H2AX maps to a cytogenetic region frequently altered in human cancers, possibly implicating similar functions in man.

journal_name

Cell

journal_title

Cell

authors

Bassing CH,Suh H,Ferguson DO,Chua KF,Manis J,Eckersdorff M,Gleason M,Bronson R,Lee C,Alt FW

doi

10.1016/s0092-8674(03)00566-x

subject

Has Abstract

pub_date

2003-08-08 00:00:00

pages

359-70

issue

3

eissn

0092-8674

issn

1097-4172

pii

S009286740300566X

journal_volume

114

pub_type

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