Anti-recombination function of MutSα restricts telomere extension by ALT-associated homology-directed repair

Alternative lengthening of telomeres (ALT) is a telomere-elongation mechanism observed in-15% of cancer subtypes. Current models indicate that ALT is mediated by homology-directed repair mechanisms. By disrupting MSH6 gene expression, we show that the deficiency of MutSa (MSH2/MSH6) DNA mismatch repair complex causes striking telomere hyperextension. Mechanistically, we show MutSa is specifically recruited to telomeres in ALT cells by associating with the proliferating-cell nuclear antigen (PCNA) subunit of the ALT telomere replisome. We also provide evidence that MutSa counteracts Bloom (BLM) helicase, which adopts a crucial role in stabilizing hyper-extended telomeres and maintaining the survival of MutSa-deficient ALT cancer cells. Lastly, we propose a model in which MutSa deficiency impairs heteroduplex rejection, leading to premature initiation of telomere DNA synthesis that coincides with an accumulation of telomere variant repeats (TVRs). These findings provide evidence that the MutSa DNA mismatch repair complex acts to restrain unwarranted ALT.

Automated summary

Alternative lengthening of telomeres (ALT) is a telomere-elongation mechanism observed in 15% of cancer subtypes. Disruption of the MutSa DNA mismatch repair complex leads to striking telomere hyperextension in ALT cells. MutSa is specifically recruited to telomeres in ALT cells by associating with the PCNA subunit of the replisome, counteracting the role of BLM helicase in stabilizing hyper-extended telomeres and maintaining the survival of MutSa-deficient ALT cancer cells.