Increased ionizing radiation sensitivity and genomic instability in the absence of histone H2AX

被引:440
作者
Bassing, CH
Chua, KF
Sekiguchi, J
Suh, H
Whitlow, SR
Fleming, JC
Monroe, BC
Ciccone, DN
Yan, C
Vlasakova, K
Livingston, DM
Ferguson, DO
Scully, R
Alt, FW [1 ]
机构
[1] Harvard Univ, Sch Med, Childrens Hosp, Howard Hughes Med,Inst Dept Genet, Boston, MA 02115 USA
[2] Ctr Blood Res, Boston, MA 02115 USA
[3] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA
[4] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Hematol & Oncol,Canc Biol Program, Boston, MA 02115 USA
关键词
D O I
10.1073/pnas.122228699
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
In mammalian cells, DNA double-strand breaks (DSBs) cause rapid phosphorylation of the H2AX core histone variant (to form gamma-H2AX) in megabase chromatin domains flanking sites of DNA damage. To investigate the role of H2AX in mammalian cells, we generated H2AX-deficient (H2AX(Delta/Delta)) mouse embryonic stem (ES) cells. H2AX(Delta/Delta) ES cells are viable. However, they are highly sensitive to ionizing radiation (IR) and exhibit elevated levels of spontaneous and IR-induced genomic instability. Notably, H2AX is not required for NHEJ per se because H2AX(Delta/Delta) ES cells support normal levels and fidelity of V(D)J recombination in transient assays and also support lymphocyte development in vivo. However, H2AX(Delta/Delta) ES cells exhibit altered IR-induced BRCA1 focus formation. Our findings indicate that H2AX function is essential for mammalian DNA repair and genomic stability.
引用
收藏
页码:8173 / 8178
页数:6
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