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MutSβ regulates G4-associated telomeric R-loops to maintain telomere integrity in ALT cancer cells
Despoina Sakellariou 1, Sara Thornby Bak 2, Esin Isik 3, Sonia I Barroso 4, Antonio Porro 3, Andrés Aguilera 4, Jiri Bartek 5, Pavel Janscak 6, Javier Peña-Diaz 7
...Emerging evidence suggests that the recombinogenic nature of ALT telomeres results from the formation of RNA:DNA hybrids (R-loops) between telomeric DNA and the long-noncoding telomeric repeat-containing RNA (TERRA). Here, we show that the mismatch repair protein MutSβ, a heterodimer of MSH2 and MSH3 subunits, is enriched at telomeres in ALT cancer cells, where it prevents the accumulation of telomeric G-quadruplex (G4) structures and R-loops. Cells depleted of MSH3 display increased incidence of R-loop-dependent telomere fragility and accumulation of telomeric C-circles. We also demonstrate that purified MutSβ recognizes and destabilizes G4 structures in vitro. These data suggest that MutSβ destabilizes G4 structures in ALT telomeres to regulate TERRA R-loops, which is a prerequisite for maintenance of telomere integrity during ALT.