MutS beta regulates G4-associated telomeric R-loops to maintain telomere integrity in ALT cancer cells

0557103 - ÚMG 2023 RIV US eng J - Článek v odborném periodiku
Sakellariou, D. - Bak, S. - Isik, E. - Barroso, S.I. - Porro, A. - Aguilera, A. - Bártek, Jiří - Janščák, Pavel - Pena-Diaz, J.
MutS beta regulates G4-associated telomeric R-loops to maintain telomere integrity in ALT cancer cells.
Cell Reports. Roč. 39, č. 1 (2022), č. článku 110602. ISSN 2211-1247. E-ISSN 2211-1247
Grant CEP: GA ČR GA19-07674S; GA ČR GA19-21325S
Institucionální podpora: RVO:68378050
Klíčová slova: mismatch-repair * replication * proteins * helicase * length * rna
Obor OECD: Cell biology
Impakt faktor: 8.8, rok: 2022
Způsob publikování: Omezený přístup
https://www.sciencedirect.com/science/article/pii/S2211124722003503?via%3Dihub

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 MutS beta, 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 MutS beta recognizes and destabilizes G4 structures in vitro. These data suggest that MutS beta destabilizes G4 structures in ALT telomeres to regulate TERRA R-loops, which is a prerequisite for maintenance of telomere integrity during ALT.
Trvalý link: http://hdl.handle.net/11104/0331414