Abstract:
: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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Prendergast L,McClurg UL,Hristova R,Berlinguer-Palmini R,Greener S,Veitch K,Hernandez I,Pasero P,Rico D,Higgins JMG,Gospodinov A,Papamichos-Chronakis Mdoi
10.1038/s41467-020-18306-xsubject
Has Abstractpub_date
2020-09-10 00:00:00pages
4534issue
1issn
2041-1723pii
10.1038/s41467-020-18306-xjournal_volume
11pub_type
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