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: In G1 or S/G2 phase, DSBs initiate a massive signaling cascade, called the DDR. The DDR sensor protein complex, MRN, recognizes damaged DNA and results in recruitment of PIKKs such as: ATM through the interaction with Nbs1; ATR through the interaction of the ATR partner, ATRIP, with replication protein A, a single-stranded DNA binding protein, on single-stranded DNAs; and a third PIKK member, DNA-PKcs, through the binding with the Ku complex, to facilitate DDR and also C-NHEJ at the DSB sites.(7) The ATM phosphorylates histone H2AX on S139, generating γH2AX (Fig. 1a).(8) The MDC1 protein recognizes γH2AX. ATM also phosphorylates MDC1 on TQXF motifs,(9) and then the RNF-containing E3 ubiquitin ligase RNF8, which mediates a protein ubiquitination cascade, is recruited to the damage site through binding to the phosphorylated TQXF motif on MDC1 (Fig. 1b, left). RNF168, a second E3 ubiquitin ligase, is accumulated at the DSB sites by recognizing products ubiquitinated by RNF8 (Fig. 1c, left). RNF8/RNF168-mediated ubiquitination of histone H2A at lysine 13/15 is believed to be important for remodeling of the chromatin flanking DSBs,(10,11) followed by RNF8/RNF168 mediated lysine 63-linked and lysine 48-linked ubiquitin chain synthesis(10,12) and multi-ubiquitination.(13) The ubiquitination cascade results in the recruitment of BRCA1 or 53BP1 to the DSB sites(14–18) (Fig. 1d, left, middle).
Affiliation: Institute for Protein Research, Osaka University, Osaka, Japan.