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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F22%3A00557103" target="_blank" >RIV/68378050:_____/22:00557103 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S2211124722003503?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S2211124722003503?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.celrep.2022.110602" target="_blank" >10.1016/j.celrep.2022.110602</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

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OECD FORD obor

10601 - Cell biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2022

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Cell Reports

ISSN

2211-1247

e-ISSN

2211-1247

Svazek periodika

39

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

19

Strana od-do

110602

Kód UT WoS článku

000785983000004

EID výsledku v databázi Scopus

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