The Fanconi Anemia Pathway Protects Genome Integrity from R-loops

Co-transcriptional rna-dna hybrids (r loops) cause genome instability. to prevent harmful r loop accumulation,cells have evolved specific eukaryotic factors,one being the brca2 double-strand break repair protein. as brca2 also protects stalled replication forks and is the fancd1 member of the fanconi anemia (fa) pathway,we investigated the fa role in r loop-dependent genome instability. using human and murine cells defective in fancd2 or fanca and primary bone marrow cells from fancd2 deficient mice,we show that the fa pathway removes r loops,and that many dna breaks accumulated in fa cells are r loop-dependent. importantly,fancd2 foci in untreated and mmc-treated cells are largely r loop dependent,suggesting that the fa functions at r loop-containing sites. we conclude that co-transcriptional r loops and r loop-mediated dna damage greatly contribute to genome instability and that one major function of the fa pathway is to protect cells from r loops. © 2015 garcía-rubio et al.