Phosphorylation of serine 1387 in Brca1 is specifically required for the Atm-mediated S-phase checkpoint after ionizing irradiation

Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Cancer Research (Impact Factor: 9.33). 09/2002; 62(16):4588-91.
Source: PubMed


Although it is well established that inheritance of mutations in the Brca1 gene significantly increases the chances of developing breast or ovarian cancers, the mechanisms underlying this specific tumor susceptibility remain to be clarified. It is clear that one of the roles of the Brca1 protein is to facilitate cellular responses to DNA damage. We recently reported that Brca1 function is required for appropriate cell cycle arrests after ionizing irradiation in both the S-phase and the G2 phase of the cell cycle. We also found that mutation of serine 1423 in Brca1, a target of Atm phosphorylation, abrogates the G2-M checkpoint but not the ionizing irradiation-induced S-phase checkpoint. Here we demonstrate that mutation of serine 1387 in Brca1, another target of Atm phosphorylation, conversely abrogates the radiation-induced S-phase arrest but does not affect the G2-M checkpoint. Thus, these two posttranslational modifications of Brca1 have two distinct functional roles in the protein. In addition, although mutation of this site abrogates the ionizing irradiation-induced S-phase arrest, it does not adversely affect cell survival after irradiation. This demonstrates that loss of this checkpoint function by itself does not affect cell survival and suggests that some other function of Brca1 alters cell survival after DNA damage.

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    • "Two tandem repeat globular domains termed BRCT, a common feature of proteins involved in the DNA damage repair and cell cycle control [5], lie at the C-terminus. Functionally, BRCA1 has been implicated in a diverse array of cellular functions, including ubiquitination [6]–[9], regulation of the G1/S [10], intra-S and G2/M-phase cell cycle checkpoint control [11]–[14], regulation of spindle pole body duplication[15], transcription [16]–[19], sex chromosome inactivation [20]–[23] and homologous recombination repair of double stranded DNA breaks [24], [25]. Taken together, these individual roles suggest a function for BRCA1 in the maintenance of genomic integrity [26], [27]. "
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    • "BRCA1 is implicated in the regulation of several cellular functions such as chromatin remodelling and DNA repair (105). BRCA1 becomes phosphorylated and, in turn, activated by ATM and ATR (106,107) and is involved in transcriptional activation of some DNA repair genes (see later in the text). BRCA1 was found to be associated with RNA polymerase II holoenzyme complex (108), thus having an impact on transcription in vitro (109). "
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    • "A defect in this checkpoint results in continued DNA synthesis, also called radioresistant DNA synthesis following IR. This checkpoint was found to require an ATM-dependent phosphorylation of BRCA1 on serine-1387 as well as a functional NBS1 (Xu et al., 2002). In addition to DNA damage-responsive checkpoints, several studies indicate that BRCA1 also regulates the mitotic spindle checkpoint by regulating gene expression associated with orderly progression through mitosis (Wang et al., 2004; Bae et al., 2005). "
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