RT Journal Article
T1 MutSβ regulates G4-associated telomeric R-loops to maintain telomere integrity in ALT cancer cells.
A1 Sakellariou, Despoina
A1 Bak, Sara Thornby
A1 Isik, Esin
A1 Barroso, Sonia I
A1 Porro, Antonio
A1 Aguilera, Andrés
A1 Bartek, Jiri
A1 Janscak, Pavel
A1 Peña-Diaz, Javier
K1 ALT cancers
K1 C-circle
K1 CP: Cancer
K1 CP: Molecular biology
K1 G-quadruplex
K1 R-loop
K1 mismatch repair
K1 telomere
AB Up to 15% of human cancers maintain their telomeres through a telomerase-independent mechanism, termed "alternative lengthening of telomeres" (ALT) that relies on homologous recombination between telomeric sequences. 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.
YR 2022
FD 2022
LK http://hdl.handle.net/10668/22075
UL http://hdl.handle.net/10668/22075
LA en
DS RISalud
RD Apr 18, 2025