Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability.

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.

• Authors: Lisa Prendergast, Urszula L McClurg, Rossitsa Hristova, Rolando Berlinguer-Palmini, Sarah Greener, Katie Veitch, Inmaculada Hernandez, Philippe Pasero, Daniel Rico, Jonathan M G Higgins, Anastas Gospodinov, Manolis Papamichos-Chronakis
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 4534 (09 10 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32913330 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• ATPases Associated with Diverse Cellular Activities
• INO80 protein, human

Topics

• ATPases Associated with Diverse Cellular Activities (metabolism)
• Apoptosis (genetics)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Cell Survival (genetics)
• Chromatin Assembly and Disassembly
• DNA Damage
• DNA Replication
• DNA-Binding Proteins (metabolism)
• Genomic Instability
• Humans
• Neoplasms (genetics, pathology)
• R-Loop Structures (genetics)
• Transcription, Genetic