The spliceosome-associated protein Nrl1 promotes DNA repair and suppresses R-loop formation in fission yeast

The formation of RNA-DNA hybrids referred as to R-loops can promote genome instability and cancer development. Yet the mechanisms by which R-loops compromise genome instability are poorly understood. Here we establish roles for the evolutionarily conserved Nrl1 protein in pre-mRNA splicing, R-loop suppression and promotion of DNA repair by homologous recombination (HR). Mutants lacking Nrl1 (nrl1?) are sensitive to both endogenous and exogenous DNA damage, and have defects in HR repair and recruitment of the HR recombinase Rad51 to DNA double strands breaks (DSB). nrl1? cells also display significant changes in gene expression similar to those induced by DNA damage. However, Nrl1 does not appear to interact with or regulate the expression of DNA repair factors. Instead, we find that R-loop formation in the absence of Nrl1 is dependent on the HR genes Rad51 and Rad52. Together, our findings support a model in which R-loop formation promotes genome instability by sequestering HR factors, thereby compromising HR repair at endogenously or exogenously induced DNA damage sites. This model may shed light on the relationship between R-loop formation and genome instability. Importantly, as the human ortholog of Nrl1 has been implicated in cancer, our analysis provides insights into how its loss may promote tumorigenesis.