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

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

doi:10.1016/j.celrep.2022.110602

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

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

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

21 Citationer (Scopus)

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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.

Originalsprog	Engelsk
Artikelnummer	110602
Tidsskrift	Cell Reports
Vol/bind	39
Udgave nummer	1
Antal sider	19
ISSN	2211-1247
DOI	https://doi.org/10.1016/j.celrep.2022.110602
Status	Udgivet - 2022

Bibliografisk note

Funding Information:
We wish to thank Kai Neelsen, Stanislaw Jozwiakowski, Andres Lopez Contreras, and Ian Hickson for critical reading of the manuscript and helpful discussions. In addition, we would like to thank Diana Odermatt and Kerstin Gari for their advice with G4 assays. J.P.D. was supported by the Danish Council for Independent Research ( DFF-4004-00117 ), the Danish Cancer Society ( R72-A4181-13-S2 ), the Nordea Foundation, Agnes and Poul Friis Fond, and Magda Sofie and Aase Lutz Mindelegat. P.J. was supported by the Swiss National Science Foundation ( 310030_184716 ) and Czech Science Foundation ( 19-07674S ). J.B. was supported by the Danish Council for Independent Research ( DFF-7016-00313 ), the Danish Cancer Society ( R204-A12617 ), the Novo Nordisk Foundation ( 200C0060590 ), the Czech Science Foundation (project 19-21325S ), the Swedish Research Council ( VR-MH 2014-46602-117891-30 ), and the Swedish CancerFonden ( no. 170176 ) and A.A. by the European Research Council ( ERC2014 AdG669898 TARLOOP ), the Spanish Ministry of Science and Innovation ( PID2019-104270GB-I00/BMC ), and the European Union (FEDER).

Publisher Copyright:
© 2022 The Author(s)

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Citationsformater

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title = "MutSβ regulates G4-associated telomeric R-loops to maintain telomere integrity in ALT cancer cells",

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.",

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

author = "Despoina Sakellariou and Bak, {Sara Thornby} and Esin Isik and Barroso, {Sonia I.} and Antonio Porro and Andr{\'e}s Aguilera and Jiri Bartek and Pavel Janscak and Javier Pe{\~n}a-Diaz",

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year = "2022",

doi = "10.1016/j.celrep.2022.110602",

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journal = "Cell Reports",

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AU - Sakellariou, Despoina

AU - Bak, Sara Thornby

AU - Isik, Esin

AU - Barroso, Sonia I.

AU - Porro, Antonio

AU - Aguilera, Andrés

AU - Bartek, Jiri

AU - Janscak, Pavel

AU - Peña-Diaz, Javier

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N2 - 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.

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.

KW - ALT cancers

KW - C-circle

KW - CP: Cancer

KW - CP: Molecular biology

KW - G-quadruplex

KW - mismatch repair

KW - R-loop

KW - telomere

U2 - 10.1016/j.celrep.2022.110602

DO - 10.1016/j.celrep.2022.110602

M3 - Journal article

C2 - 35385755

AN - SCOPUS:85127494863

SN - 2211-1247

VL - 39

JO - Cell Reports

JF - Cell Reports

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