Double-strand break repair-adox: Restoration of suppressed double-strand break repair during mitosis induces genomic instability.
Bottom Line: The failure of this process often results in apoptosis or genomic instability, such as aneuploidy, deletion, or translocation.The biological significance of this suppression is not known.We discuss how DSBs during mitosis are toxic and the multiple safeguard systems that suppress genomic instability.
Affiliation: Institute for Protein Research, Osaka University, Osaka, Japan.Show MeSH
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Mentions: During mitosis, DSBs activate PIKKs to induce phosphorylation of H2AX, and MDC1 as well as the MRN complex are recruited to the DSB sites, as seen during interphases (Fig. 1a). However, the recruitment of RNF8, RNF168, 53BP1, and BRCA1 to DSB is largely suppressed during mitosis (Fig. 1b,d, right).(30,33) The mechanism of the suppression and its purpose were not well understood. Two groups recently showed that localization of RNF8 and 53BP1 to DSBs is inhibited during mitosis.(35,36) The first work done by Orthwein et al. (2014) showed that, in human cells, RNF8 and 53BP1 are phosphorylated during mitosis by CDK1 and that inhibition of the phosphorylation restores their localization to DSB sites (Fig. 1b,d, right). Orthwein et al. also identified T198 on RNF8 as a CDK1 phosphorylation site and showed that RNF8-T198A, a phosphorylation-defective protein, can localize to mitotic chromatin after DSB introduction. RNF8 prepared from mitotic extracts cannot bind to MDC1 in vitro, but RNF8 prepared from CDK1 activity-inhibited cells interacts with MDC1 in vitro. The RNF8-T198A protein restores localization of BRCA1 but not 53BP1 to the DSB site. They also found that T1609 and S1618 on 53BP1 are phosphorylated during mitosis (Fig. 3a) and that 53BP1-T1609A/S1618A double mutant protein can localize to mitotic chromatin and restores DSB repair in cells expressing RNF8-T198A. Their study confirmed that T1609 is phosphorylated by CDK1, whereas S1618 is a target of PLK1 in vitro. These show that there are at least two distinct mechanisms to regulate the recruitment of these DDR effector proteins.(35)
Affiliation: Institute for Protein Research, Osaka University, Osaka, Japan.