Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors.
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.
Bassing
Craig H
CH
Howard Hughes Medical Institute, The Children's Hospital, Department of Genetics, Harvard Medical School and The Center for Blood Research, Boston, MA 02115, USA.
Suh
Heikyung
H
Ferguson
David O
DO
Chua
Katrin F
KF
Manis
John
J
Eckersdorff
Mark
M
Gleason
Megan
M
Bronson
Rodrick
R
Lee
Charles
C
Alt
Frederick W
FW
D000818:Animals; D001483:Base Sequence; D002843:Chromatin; D004249:DNA Damage; D004260:DNA Repair; D018390:Gene Targeting; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D009857:Oncogenes; D016415:Sequence Alignment; D015996:Survival Rate; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D002843:Chromatin; D006657:Histones; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C475961:gamma-H2AX protein, mouse