Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability
Collisions between the DNA replication machinery and co-transcriptional R-loops can impede DNA synthesis and are a major source of genomic instability in cancer cells. How cancer cells deal with R-loops to proliferate is poorly understood. Here we show that the ATP-dependent chromatin remodelling INO80 complex promotes resolution of R-loops to prevent replication-associated DNA damage in cancer cells. Depletion of INO80 in prostate cancer PC3 cells leads to increased R-loops. Overexpression of the RNA:DNA endonuclease RNAse H1 rescues the DNA synthesis defects and suppresses DNA damage caused by INO80 depletion. R-loops co-localize with and promote recruitment of INO80 to chromatin. Artificial tethering of INO80 to a LacO locus enabled turnover of R-loops in cis. Finally, counteracting R-loops by INO80 promotes proliferation and averts DNA damage-induced death in cancer cells. Our work suggests that INO80-dependent resolution of R-loops promotes DNA replication in the presence of transcription, thus enabling unlimited proliferation in cancers.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
Nature communications - 11(2020), 1 vom: 10. Sept., Seite 4534 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Prendergast, Lisa [VerfasserIn] |
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| Links: |
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| Themen: |
ATPases Associated with Diverse Cellular Activities |
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| Anmerkungen: |
Date Completed 30.09.2020 Date Revised 28.04.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-020-18306-x |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Collisions between the DNA replication machinery and co-transcriptional R-loops can impede DNA synthesis and are a major source of genomic instability in cancer cells. How cancer cells deal with R-loops to proliferate is poorly understood. Here we show that the ATP-dependent chromatin remodelling INO80 complex promotes resolution of R-loops to prevent replication-associated DNA damage in cancer cells. Depletion of INO80 in prostate cancer PC3 cells leads to increased R-loops. Overexpression of the RNA:DNA endonuclease RNAse H1 rescues the DNA synthesis defects and suppresses DNA damage caused by INO80 depletion. R-loops co-localize with and promote recruitment of INO80 to chromatin. Artificial tethering of INO80 to a LacO locus enabled turnover of R-loops in cis. Finally, counteracting R-loops by INO80 promotes proliferation and averts DNA damage-induced death in cancer cells. Our work suggests that INO80-dependent resolution of R-loops promotes DNA replication in the presence of transcription, thus enabling unlimited proliferation in cancers | ||
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| 700 | 1 | |a Hristova, Rossitsa |e verfasserin |4 aut | |
| 700 | 1 | |a Berlinguer-Palmini, Rolando |e verfasserin |4 aut | |
| 700 | 1 | |a Greener, Sarah |e verfasserin |4 aut | |
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| 700 | 1 | |a Gospodinov, Anastas |e verfasserin |4 aut | |
| 700 | 1 | |a Papamichos-Chronakis, Manolis |e verfasserin |4 aut | |
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