P53 Binding Protein 1 (53bp1) Is an Early Participant in the Cellular Response to DNA Double-Strand Breaks

By L. B. Schultz, N. Chehab, Asra Malikzay, T. Halazonetis. Journal of Cell Biology, 2000

963 citations recorded by the source corpus.

p53 binding protein 1 (53BP1), a protein proposed to function as a transcriptional coactivator of the p53 tumor suppressor, has BRCT domains with high homology to the Saccharomyces cerevisiae Rad9p DNA damage checkpoint protein. To examine whether 53BP1 has a role in the cellular response to DNA damage, we probed its intracellular localization by immunofluorescence. In untreated primary cells and U2OS osteosarcoma cells, 53BP1 exhibited diffuse nuclear staining; whereas, within 5–15 min after exposure to ionizing radiation (IR), 53BP1 localized at discreet nuclear foci. We propose that these foci represent sites of processing of DNA double-strand breaks (DSBs), because they were induced by IR and chemicals that cause DSBs, but not by ultraviolet light; their peak number approximated the number of DSBs induced by IR and decreased over time with kinetics that parallel the rate of DNA repair; and they colocalized with IR-induced Mre11/NBS and γ-H2AX foci, which have been previously shown to localize at sites of DSBs. Formation of 53BP1 foci after irradiation was not dependent on ataxia-telangiectasia mutated (ATM), Nijmegen breakage syndrome (NBS1), or wild-type p53. Thus, the fast kinetics of 53BP1 focus formation after irradiation and the lack of dependency on ATM and NBS1 suggest that 53BP1 functions early in the cellular response to DNA DSBs.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/604afdcb7dc53002554c0238072a04e158316eb0

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Citations in the corpus

Mechanism and regulation of class switch recombination. (2008, background): “DNA-PK, which consists of Ku70–Ku80 and DNA-PKcs, most likely binds DSB ends first.”
Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks (2004, methodology): “The data were determined from four independent experiments of control (Ctrl) siRNA-treated cells or cells transfected once (1) or three consecutive times (3) with DOT1L-specific siRNA.”
MDC1 is a mediator of the mammalian DNA damage checkpoint (2003, background): “However, several large BRCT-repeat-containing proteins, such as TopBP1, 53BP1 and BRCA1, which have been implicated in the cellular response to DNA damage, may compose this class of mediator protein in higher eukaryotic cell”
An improved zinc-finger nuclease architecture for highly specific genome editing (2007, methodology): “Our initial studies used detection of the protein 53BP1, which localizes to sites of DNA damage and forms foci that may be visualized by immunofluorescenc”
Cell cycle checkpoint signaling through the ATM and ATR kinases. (2001, background): “The p53 binding protein 1 (53BP1) is a nuclear protein that rapidly localizes to sites of DNA damage in cells treated with IR and other DNA-damaging agents (Schultz et al. 2000; Rappold et al. 2001).”
Regulation and mechanisms of mammalian double-strand break repair (2003, background): “Other recently identified proteins that seem important for DSB sensing and focus formation are the 53BP1 and NFBD1/KIAA0170 proteins (Iwabuchi et al., 1994; Schultz et al., 2000; Anderson et al., 2001; Rappold et al., 2001; Xu and Stern, 2002).”
Systematic discovery of in vivo phosphorylation networks. (2007, background): “For instance, we predict several kinases for the 53BP1 protein that has been shown to accumulate at DNA damage-induced foci and to be hyperphosphorlylated in an ATM-dependent manner (Anderson et al., 2001; Rappold et al., 2001; Schultz et al., 2000).”
Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks (2003, background): “In contrast to Nbs1, 53BP1 forms IRIF very rapidly, which colocalize with γ-H2AX foc”