MutSβ regulates G4-associated telomeric R-loops to maintain telomere integrity in ALT cancer cells
Language English Country United States Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
35385755
DOI
10.1016/j.celrep.2022.110602
PII: S2211-1247(22)00350-3
Knihovny.cz E-resources
- Keywords
- ALT cancers, C-circle, CP: Cancer, CP: Molecular biology, G-quadruplex, R-loop, mismatch repair, telomere,
- MeSH
- DNA metabolism MeSH
- Telomere Homeostasis MeSH
- Humans MeSH
- Neoplasms * genetics MeSH
- R-Loop Structures MeSH
- RNA, Long Noncoding * metabolism MeSH
- Telomere metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- DNA MeSH
- RNA, Long Noncoding * MeSH
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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