Genomic instability in mice lacking histone H2AX.
Higher order chromatin structure presents a barrier to the recognition and repair of DNA damage. Double-strand breaks (DSBs) induce histone H2AX phosphorylation, which is associated with the recruitment of repair factors to damaged DNA. To help clarify the physiological role of H2AX, we targeted H2AX in mice. Although H2AX is not essential for irradiation-induced cell-cycle checkpoints, H2AX-/- mice were radiation sensitive, growth retarded, and immune deficient, and mutant males were infertile. These pleiotropic phenotypes were associated with chromosomal instability, repair defects, and impaired recruitment of Nbs1, 53bp1, and Brca1, but not Rad51, to irradiation-induced foci. Thus, H2AX is critical for facilitating the assembly of specific DNA-repair complexes on damaged DNA.
Celeste
Arkady
A
Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Petersen
Simone
S
Romanienko
Peter J
PJ
Fernandez-Capetillo
Oscar
O
Chen
Hua Tang
HT
Sedelnikova
Olga A
OA
Reina-San-Martin
Bernardo
B
Coppola
Vincenzo
V
Meffre
Eric
E
Difilippantonio
Michael J
MJ
Redon
Christophe
C
Pilch
Duane R
DR
Olaru
Alexandru
A
Eckhaus
Michael
M
Camerini-Otero
R Daniel
RD
Tessarollo
Lino
L
Livak
Ferenc
F
Manova
Katia
K
Bonner
William M
WM
Nussenzweig
Michel C
MC
Nussenzweig
André
A
D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology; D001483:Base Sequence; D002453:Cell Cycle; D002478:Cells, Cultured; D016922:Cellular Senescence; D002869:Chromosome Aberrations; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D018390:Gene Targeting; D006657:Histones / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D017578:Immunoglobulin Class Switching; D007248:Infertility, Male / Q000235:genetics / Q000503:physiopathology; D018655:Lymphocyte Count; D008297:Male; D008540:Meiosis; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D011995:Recombination, Genetic; D013090:Spermatocytes / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology
D006657:Histones