DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1.
Activation of the ataxia telangiectasia mutated (ATM) kinase triggers diverse cellular responses to ionizing radiation (IR), including the initiation of cell cycle checkpoints. Histone H2AX, p53 binding-protein 1 (53BP1) and Chk2 are targets of ATM-mediated phosphorylation, but little is known about their roles in signalling the presence of DNA damage. Here, we show that mice lacking either H2AX or 53BP1, but not Chk2, manifest a G2-M checkpoint defect close to that observed in ATM(-/-) cells after exposure to low, but not high, doses of IR. Moreover, H2AX regulates the ability of 53BP1 to efficiently accumulate into IR-induced foci. We propose that at threshold levels of DNA damage, H2AX-mediated concentration of 53BP1 at double-strand breaks is essential for the amplification of signals that might otherwise be insufficient to prevent entry of damaged cells into mitosis.
Fernandez-Capetillo
Oscar
O
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Chen
Hua-Tang
HT
Celeste
Arkady
A
Ward
Irene
I
Romanienko
Peter J
PJ
Morales
Julio C
JC
Naka
Kazuhito
K
Xia
Zhenfang
Z
Camerini-Otero
R Daniel
RD
Motoyama
Noboru
N
Carpenter
Phillip B
PB
Bonner
William M
WM
Chen
Junjie
J
Nussenzweig
André
A
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D002460:Cell Line; D064447:Checkpoint Kinase 2; D002868:Chromosomal Proteins, Non-Histone; D004249:DNA Damage / Q000235:genetics*; D004268:DNA-Binding Proteins; D016195:G2 Phase / Q000235:genetics* / Q000502:physiology; D005786:Gene Expression Regulation; D006657:Histones / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008938:Mitosis / Q000235:genetics* / Q000502:physiology; D010750:Phosphoproteins; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D000071857:Tumor Suppressor p53-Binding Protein 1
D002352:Carrier Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases