1. The spliceosome-associated protein Nrl1 suppresses homologous recombination-dependent R-loop formation in fission yeast.
- Author
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Aronica L, Kasparek T, Ruchman D, Marquez Y, Cipak L, Cipakova I, Anrather D, Mikolaskova B, Radtke M, Sarkar S, Pai CC, Blaikley E, Walker C, Shen KF, Schroeder R, Barta A, Forsburg SL, and Humphrey TC
- Subjects
- DNA chemistry, DNA genetics, DNA Repair genetics, RNA chemistry, RNA genetics, Rad51 Recombinase genetics, Rad52 DNA Repair and Recombination Protein genetics, Schizosaccharomyces genetics, Spliceosomes genetics, Spliceosomes metabolism, Alternative Splicing genetics, Genomic Instability genetics, Homologous Recombination genetics, RNA Precursors genetics, Schizosaccharomyces pombe Proteins genetics
- Abstract
The formation of RNA-DNA hybrids, referred to as 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 regulation, R-loop suppression and in maintaining genome stability. nrl1Δ mutants exhibit endogenous DNA damage, are sensitive to exogenous DNA damage, and have defects in homologous recombination (HR) repair. Concomitantly, nrl1Δ cells display significant changes in gene expression, similar to those induced by DNA damage in wild-type cells. Further, we find that nrl1Δ cells accumulate high levels of R-loops, which co-localize with HR repair factors and require Rad51 and Rad52 for their formation. Together, our findings support a model in which R-loop accumulation and subsequent DNA damage sequesters HR factors, thereby compromising HR repair at endogenously or exogenously induced DNA damage sites, leading to genome instability., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2016
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