Harmful R-loops are prevented via different cell cycle-specific mechanisms.

Identifying how R-loops are generated is crucial to know how transcription compromises genome integrity. We show by genome-wide analysis of conditional yeast mutants that the THO transcription complex, prevents R-loop formation in G1 and S-phase, whereas the Sen1 DNA-RNA helicase prevents them only in S-phase. Interestingly, damage accumulates asymmetrically downstream of the replication fork in sen1 cells but symmetrically in the hpr1 THO mutant.

ELOF1 is a transcription-coupled DNA repair factor that directs RNA polymerase II ubiquitylation.

Cells employ transcription-coupled repair (TCR) to eliminate transcription-blocking DNA lesions. DNA damage-induced binding of the TCR-specific repair factor CSB to RNA polymerase II (RNAPII) triggers RNAPII ubiquitylation of a single lysine (K1268) by the CRL4 ubiquitin ligase. How CRL4 is specifically directed towards K1268 is unknown.

Untangling the crosstalk between BRCA1 and R-loops during DNA repair.

R-loops are RNA:DNA hybrids assembled during biological processes but are also linked to genetic instability when formed out of their natural context. Emerging evidence suggests that the repair of DNA double-strand breaks requires the formation of a transient R-loop, which eventually must be removed to guarantee a correct repair process. The multifaceted BRCA1 protein has been shown to be recruited at this specific break-induced R-loop, and it facilitates mechanisms in order to regulate R-loop removal.

Harmful DNA:RNA hybrids are formed and in a Rad51-independent manner.

DNA:RNA hybrids constitute a well-known source of recombinogenic DNA damage. The current literature is in agreement with DNA:RNA hybrids being produced co-transcriptionally by the invasion of the nascent RNA molecule produced in cis with its DNA template. However, it has also been suggested that recombinogenic DNA:RNA hybrids could be facilitated by the invasion of RNA molecules produced in trans in a Rad51-mediated reaction.

Histone H3E73Q and H4E53A mutations cause recombinogenic DNA damage.

The stability and function of eukaryotic genomes is closely linked to histones and to chromatin structure. The state of the chromatin not only affects the probability of DNA to undergo damage but also DNA repair. DNA damage can result in genetic alterations and subsequent development of cancer and other genetic diseases.

The Antitumor Drugs Trabectedin and Lurbinectedin Induce Transcription-Dependent Replication Stress and Genome Instability.

R-loops are a major source of replication stress, DNA damage, and genome instability, which are major hallmarks of cancer cells. Accordingly, growing evidence suggests that R-loops may also be related to cancer. Here we show that R-loops play an important role in the cellular response to trabectedin (ET743), an anticancer drug from marine origin and its derivative lurbinectedin (PM01183).