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MutSβ regulates G4-associated telomeric R-loops to maintain telomere integrity in ALT cancer cells.

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2022

Authors

Sakellariou, Despoina
Bak, Sara Thornby
Isik, Esin
Barroso, Sonia I
Porro, Antonio
Aguilera, Andrés
Bartek, Jiri
Janscak, Pavel
Peña-Diaz, Javier

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Abstract

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.

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MeSH Terms

DNA
Humans
Neoplasms
R-Loop Structures
RNA, Long Noncoding
Telomere
Telomere Homeostasis

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Keywords

ALT cancers, C-circle, CP: Cancer, CP: Molecular biology, G-quadruplex, R-loop, mismatch repair, telomere

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