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: Cells prevent carryover of DNA lesions at the G2/M checkpoint because DNA damage as well as the DNA repair process are toxic during mitosis. As described above, there are several types of DSB repair suppression systems that occur during mitosis. The DDR pathway consists of two steps (Fig. 4a). However, mitotic cells do not undergo the second level of DDR: neither 53BP1 nor BRCA1 localizes to DSB sites. Mitosis-specific phosphorylation of 53BP1 and RNF8 prevents their localization to DSB sites.(35,36) Because 53BP1 and BRCA1 localization to DSB sites is important for NHEJ and HR, respectively, DSB repair pathways should be largely suppressed on mitotic chromosomes (Fig. 4b). We found that the third level of DDR is also suppressed or modified by mitosis-specific phosphorylation of XRCC4, a component of the core C-NHEJ complex.(38) Even if DSB repair pathways are largely suppressed by mitosis-specific phosphorylation of 53BP1 and RNF8, considerable levels of DSB repair still occur and cause genomic instability during mitosis. Phosphorylation of XRCC4 during mitosis slows DSB repair.(38) Thus, XRCC4 phosphorylation has some functions to modulate DNA ligase IV complex activity (Fig. 4c). In addition, XRCC4 fails to localize to mitotic chromatin.(54) The failure of XRCC4 to localize to mitotic chromosomes also may modify the composition of the DNA ligase IV complex. CtIP, but not Rad51, is recruited to mitotic chromatin.(53) This also suggests that there is the third level of suppression mechanisms in HR and that CtIP has some functions to prevent genomic instability without the requirement of BRCA1 localization.
Affiliation: Institute for Protein Research, Osaka University, Osaka, Japan.