BLM-dependent Break-Induced Replication handles DSBs in transcribed chromatin upon impaired RNA:DNA hybrids dissolution

Abstract

Transcriptionally active loci are particularly prone to breakage and mounting evidence suggest that DNA Double-Strand Breaks arising in genes are handled by a dedicated repair pathway, Transcription-Coupled DSB Repair (TC-DSBR), that entails R-loops accumulation and dissolution. Here, we uncovered a critical function of the Bloom RecQ DNA helicase (BLM) in TC-DSBR in human cells. BLM is recruited in a transcription dependent-manner at DSBs where it fosters resection, RAD51 binding and accurate Homologous Recombination repair. However, in a R-loop dissolution-deficient background BLM switches from promoting Homologous Recombination to promoting Break-Induced Replication (BIR), which strongly impairs cell viability. Altogether our

Mechanisms of Genome Instability in the Fragile X-Related Disorders

“…Multiple template-switching events, which are known to occur at the early stages of BIR, could also potentially result in the gain or loss of repeats. While BIR is usually involved in the repair of one-ended breaks originating at a stalled replication fork, it has been suggested that BIR can be initiated at double-strand breaks induced in R-loops [87]. Thus, a BIR-dependent process triggered by an R-loop may allow expansion in both dividing and non-dividing cells [88].…”