DNMT3b Dysfunction Promotes DNA cleavages at Centromeric R-loops to Increase Centromere Instability
Shih, H.-T.; Chen, W.-Y.; Wang, H.-Y.; Huang, H.-D.; Chou, C.-H.; Chang, Z.-F.
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This study investigates how DNA methyltransferase 3b (DNMT3b) dysfunction causes genome instability. We showed that in DNMT3b deficient cells, R-loops contribute to prominent {gamma}H2AX signal, which was mapped to repetitive satellite sequences including centromere regions. By ChIP and DRIP analyses, our data revealed that centromeric R-loops in DNMT3b deficient cells are removed by XPG/XPF, thus generating DNA breaks in centromeres to increase mitotic aberration. In immunodeficiency-centromeric instability-facial anomalies (ICF) patient cells carrying the loss-of-function mutation at DNMT3b, knockdown of XPG/XPF in ICF cells also reduces DNA breaks in centromere while bringing up centromeric R-loop to the level similar to that in wild-type cells. These results suggest that DNMT3b has a critical function in preventing XPG/XPF-mediated cleavages at centromeric R-loop sites. Finally, we showed the involvement of non-homologous end-joining repair at centromeric sites in ICF cells. Thus, DNA cleavages at centromeric R-loops with error-prone repair undermine centromere stability in ICF cells.
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