Understanding R loop-mediated genome instability: a new role for histones and chromatin modifications

Abstract

Resumen del trabajo presentado a la 12th International Conference & 5th Asian Congress on Environmental Mutagens with the 33rd Annual Meeting of KSOT/KEMS, celebradas en Songdo Convensia, Incheon (Korea) del 12 al 16 de noviembre de 2017.Coordination of DNA replication with DNA-damage sensing, repair and cell cycle progression ensures with high probability genome integrity during cell divisions. One important type of genome instability is that associated with transcription. R loops, structures formed by a DNA-RNA hybrid and the displaced single-stranded DNA (ssDNA) molecule, are transcriptional by-products that can be formed naturally as key intermediates in specific cellular processes. Nevertheless, they are also a major source of transcription-associated genome instability and compelling evidence supports that this is mainly caused by replication fork impairment. Consequently, the relevance of R loopmediated genome instability as a mechanism of environmental mutagenesis needs to be studied. Our analysis of R loop-mediated instability in human cells depleted of the THO complex involved in RNA biogenesis reveals a new role for chromatin modifications in R loop accumulation. In addition, using human activation-induced cytidine deaminase (AID), we have identified yeast histone mutants that facilitate R loop formation without leading to genome instability. These R loops are similar in size to those causing genome instability. However, these yeast histone mutants do not lead to the same chromatin alterations. Importantly, we are able to suppress R loop-mediated genome instability by specific histone mutations as well as by altering the pattern of co-transcriptional chromatin modifications in yeast and human cells. Our results imply a new role for chromatin on the sources or R loop formation as well as on the mechanisms of transcription-associated genome instability. The relevance of our conclusions in the context of environmental genotoxicity will be discussed.Peer Reviewe