Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage
- PMID: 9267023
- DOI: 10.1016/s0092-8674(00)80503-6
Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage
Abstract
BRCA1 localizes to discrete nuclear foci (dots) during S phase. Hydroxyurea-mediated DNA synthesis arrest of S phase MCF7 cells led to a loss of BRCA1 from these structures. Ultraviolet light, mitomycin C, or gamma irradiation produced a similar effect but with no concurrent arrest of DNA synthesis. BARD1 and Rad51, two proteins associated with the BRCA1 dots, behaved similarly. Loss of the BRCA1 foci was accompanied by a specific, dose-dependent change(s) in the state of BRCA1 phosphorylation. Three distinct DNA damaging agents preferentially induced this change in S phase. The S phase BRCA1 phosphorylation response to DNA damage occurred in cells lacking, respectively, two DNA damage-sensing protein kinases, DNA-PK and Atm, implying that neither plays a prime role in this process. Finally, after BRCA1 dot dispersal, BRCA1, BARD1, and Rad51 accumulated, focally, on PCNA+ replication structures, implying an interaction of BRCA1/BARD1/Rad51 containing complexes with damaged, replicating DNA. Taken together, the data imply that the BRCA1 S phase foci are dynamic physiological elements, responsive to DNA damage, and that BRCA1-containing multiprotein complexes participate in a replication checkpoint response.
Similar articles
-
BRCA1-BARD1 complexes are required for p53Ser-15 phosphorylation and a G1/S arrest following ionizing radiation-induced DNA damage.J Biol Chem. 2004 Jul 23;279(30):31251-8. doi: 10.1074/jbc.M405372200. Epub 2004 May 24. J Biol Chem. 2004. PMID: 15159397
-
PI 3 kinase related kinases-independent proteolysis of BRCA1 regulates Rad51 recruitment during genotoxic stress in human cells.PLoS One. 2010 Nov 17;5(11):e14027. doi: 10.1371/journal.pone.0014027. PLoS One. 2010. PMID: 21103343 Free PMC article.
-
Ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3 related kinase mediate phosphorylation of Brca1 at distinct and overlapping sites. In vivo assessment using phospho-specific antibodies.J Biol Chem. 2001 May 18;276(20):17276-80. doi: 10.1074/jbc.M011681200. Epub 2001 Feb 13. J Biol Chem. 2001. PMID: 11278964
-
Localization of BRCA1 protein at the cellular level.J Mammary Gland Biol Neoplasia. 1998 Oct;3(4):423-9. doi: 10.1023/a:1018740216630. J Mammary Gland Biol Neoplasia. 1998. PMID: 10819536 Review.
-
BRCA1 phosphorylation: biological consequences.Cancer Biol Ther. 2006 May;5(5):470-5. doi: 10.4161/cbt.5.5.2845. Epub 2006 May 30. Cancer Biol Ther. 2006. PMID: 16721040 Review.
Cited by
-
High expression of PPP1CC promotes NHEJ-mediated DNA repair leading to radioresistance and poor prognosis in nasopharyngeal carcinoma.Cell Death Differ. 2024 May;31(5):683-696. doi: 10.1038/s41418-024-01287-5. Epub 2024 Apr 8. Cell Death Differ. 2024. PMID: 38589496
-
BRCA1 and NORE1A Form a Her2/Ras Regulated Tumor Suppressor Complex Modulating Senescence.Cancers (Basel). 2023 Aug 16;15(16):4133. doi: 10.3390/cancers15164133. Cancers (Basel). 2023. PMID: 37627161 Free PMC article.
-
BRCA1/BARD1 intrinsically disordered regions facilitate chromatin recruitment and ubiquitylation.EMBO J. 2023 Aug 1;42(15):e113565. doi: 10.15252/embj.2023113565. Epub 2023 Jun 12. EMBO J. 2023. PMID: 37305927 Free PMC article.
-
Cancer and Radiosensitivity Syndromes: Is Impaired Nuclear ATM Kinase Activity the Primum Movens?Cancers (Basel). 2022 Dec 13;14(24):6141. doi: 10.3390/cancers14246141. Cancers (Basel). 2022. PMID: 36551628 Free PMC article. Review.
-
BRCA1 mediates protein homeostasis through the ubiquitination of PERK and IRE1.iScience. 2022 Nov 19;25(12):105626. doi: 10.1016/j.isci.2022.105626. eCollection 2022 Dec 22. iScience. 2022. PMID: 36471805 Free PMC article.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials
Miscellaneous