RECQL5 Controls Transcript Elongation and Suppresses Genome Instability Associated with Transcription Stress

Abstract

SummaryRECQL5 is the sole member of the RECQ family of helicases associated with RNA polymerase II (RNAPII). We now show that RECQL5 is a general elongation factor that is important for preserving genome stability during transcription. Depletion or overexpression of RECQL5 results in corresponding shifts in the genome-wide RNAPII density profile. Elongation is particularly affected, with RECQL5 depletion causing a striking increase in the average rate, concurrent with increased stalling, pausing, arrest, and/or backtracking (transcription stress). RECQL5 therefore controls the movement of RNAPII across genes. Loss of RECQL5 also results in the loss or gain of genomic regions, with the breakpoints of lost regions located in genes and common fragile sites. The chromosomal breakpoints overlap with areas of elevated transcription stress, suggesting that RECQL5 suppresses such stress and its detrimental effects, and thereby prevents genome instability in the transcribed region of genes.

Mutation of cancer driverMLL2results in transcription stress and genome instability

“…RECQL5 has a well-established role in maintaining genomic stability (Aygun and Svejstrup 2010;Saponaro et al 2014). While the mechanistic relevance of MLL2-RECQL5 interaction is yet to be investigated, the connection spurred us to investigate the potential role of MLL2 in the maintenance of genome integrity.…”

“…We recently reported that RECQL5, a member of the RECQ family of helicases, is a general RNA polymerase II (RNAPII) elongation factor that is important for preserving genomic stability during transcription (Saponaro et al 2014). Indeed, depletion of RECQL5 results in increased pausing, stalling, arrest, and/or backtracking (collectively referred to as transcription stress) at sites that overlap with regions of genome instability.…”

“…As it transcribes through nucleosomes, RNAPII interacts with chromatin-modifying enzymes, affecting chromatin structure and nucleosome displacement/reassembly. In the absence of tightly regulated cotranscriptional chromatin rearrangement, transcript elongation can be interrupted, resulting in transcription stress and potential disturbance of the integrity of the transcribed region (Svejstrup 2007;Selth et al 2010;Saponaro et al 2014). In light of these considerations, it is intriguing that mutations in chromatin-regulating enzymes have been identified in several recent cancer genome-sequencing projects (for recent reviews, see Roy et al 2014;Van Rechem and Whetstine 2014).…”

RECQ5-dependent SUMOylation of DNA topoisomerase I prevents transcription-associated genome instability

“…RECQ5 prevents transcription-associated DSBs by suppressing RNAPII-dependent transcription initiation 18 , and this may be achieved by the interaction between RNAPII and the RECQ5 KIX domain, which blocks the binding of transcription elongation factor TFIIS to RNAPII 19 . RECQ5 is also known to interact with the active RNAPII (RNAPIIo) elongation complex to maintain the transcription elongation rate and prevent genome instability 15,20,21 . However, the exact mechanism by which RECQ5 maintains genome stability during transcription elongation has also not been determined.…”

Replication stress and cancer: It takes two to tango

“…A recent paper has shown that RECQL5 slows down RNA polymerase II elongation and increases the robustness of transcription. Depletion of RECQL5 increases polymerase pausing and leads to genomic instability with gains and losses in common fragile sites and long genes, further supporting that stalled forks, regardless of the cause, can ultimately derive into pro-tumoral mutations [58]. These data suggest that RECQL5 may be limiting the generation of R-loops, yet further analyses should address this point.…”