title: DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1.
abstract: 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.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernandez-Capetillo
authors.forename: Hua-Tang
authors.initials: HT
authors.lastname: Chen
authors.forename: Arkady
authors.initials: A
authors.lastname: Celeste
authors.forename: Irene
authors.initials: I
authors.lastname: Ward
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Romanienko
authors.forename: Julio C
authors.initials: JC
authors.lastname: Morales
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Naka
authors.forename: Zhenfang
authors.initials: Z
authors.lastname: Xia
authors.forename: R Daniel
authors.initials: RD
authors.lastname: Camerini-Otero
authors.forename: Noboru
authors.initials: N
authors.lastname: Motoyama
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Carpenter
authors.forename: William M
authors.initials: WM
authors.lastname: Bonner
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen
authors.forename: André
authors.initials: A
authors.lastname: Nussenzweig
mesh_terms: 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
chemical_list: 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