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Double-strand break repair-adox: Restoration of suppressed double-strand break repair during mitosis induces genomic instability.

Terasawa M, Shinohara A, Shinohara M - Cancer Sci. (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Institute for Protein Research, Osaka University, Osaka, Japan.

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DNA damage response in mitosis. (a) Double-strand break (DSB) induces histone H2AX phosphorylation (γH2AX) by ATM. (b) CDK1 and PLK1 phosphorylate RNF8 and 53BP1 to inhibit 53BP1 and BRCA1 localization of DSB sites. (c) CDK1 and PLK1 phosphorylate XRCC4, a regulatory subunit of the DNA ligase IV complex, to suppress canonical non-homologous end joining (C-NHEJ) activity. CtIP-dependent alternative non-homologous end joining (A-NHEJ) may prevent anaphase bridge formation.
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fig04: DNA damage response in mitosis. (a) Double-strand break (DSB) induces histone H2AX phosphorylation (γH2AX) by ATM. (b) CDK1 and PLK1 phosphorylate RNF8 and 53BP1 to inhibit 53BP1 and BRCA1 localization of DSB sites. (c) CDK1 and PLK1 phosphorylate XRCC4, a regulatory subunit of the DNA ligase IV complex, to suppress canonical non-homologous end joining (C-NHEJ) activity. CtIP-dependent alternative non-homologous end joining (A-NHEJ) may prevent anaphase bridge formation.

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.


Double-strand break repair-adox: Restoration of suppressed double-strand break repair during mitosis induces genomic instability.

Terasawa M, Shinohara A, Shinohara M - Cancer Sci. (2014)

DNA damage response in mitosis. (a) Double-strand break (DSB) induces histone H2AX phosphorylation (γH2AX) by ATM. (b) CDK1 and PLK1 phosphorylate RNF8 and 53BP1 to inhibit 53BP1 and BRCA1 localization of DSB sites. (c) CDK1 and PLK1 phosphorylate XRCC4, a regulatory subunit of the DNA ligase IV complex, to suppress canonical non-homologous end joining (C-NHEJ) activity. CtIP-dependent alternative non-homologous end joining (A-NHEJ) may prevent anaphase bridge formation.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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fig04: DNA damage response in mitosis. (a) Double-strand break (DSB) induces histone H2AX phosphorylation (γH2AX) by ATM. (b) CDK1 and PLK1 phosphorylate RNF8 and 53BP1 to inhibit 53BP1 and BRCA1 localization of DSB sites. (c) CDK1 and PLK1 phosphorylate XRCC4, a regulatory subunit of the DNA ligase IV complex, to suppress canonical non-homologous end joining (C-NHEJ) activity. CtIP-dependent alternative non-homologous end joining (A-NHEJ) may prevent anaphase bridge formation.
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.

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.

View Article: PubMed Central - PubMed

Affiliation: Institute for Protein Research, Osaka University, Osaka, Japan.

Show MeSH
Related in: MedlinePlus