RECQ5: A Mysterious Helicase at the Interface of DNA Replication and Transcription

Abstract

RECQ5 belongs to the RecQ family of DNA helicases. It is conserved from Drosophila to humans and its deficiency results in genomic instability and cancer susceptibility in mice. Human RECQ5 is known for its ability to regulate homologous recombination by disrupting RAD51 nucleoprotein filaments. It also binds to RNA polymerase II (RNAPII) and negatively regulates transcript elongation by RNAPII. Here, we summarize recent studies implicating RECQ5 in the prevention and resolution of transcription-replication conflicts, a major intrinsic source of genomic instability during cancer development.

Keywords: DNA repair; R-loops; RECQ5; genomic instability; replication stress; transcription-replication conflicts.

Figure 1

Domain organization of human RECQ5 helicase. For description of the individual domains see the main text. The positions of amino acids at domain boundaries are indicated.

Figure 2

Proposed model for the role of RECQ5 in the suppression of crossovers during homologous recombination repair. RECQ5 promotes the SDSA sub-pathway of HR by disrupting RAD51 filaments formed on ssDNA after RTEL1-mediated unwinding of the extended D-loop. This prevents D-loop reassembly and its conversion to double-Holliday junction, which can be resolved to crossover (CO) or non-crossover (NCO) products.

Figure 3

Proposed roles for RECQ5 in resolution of transcription-replication conflicts. (A) Role of RECQ5 in resolution of R-loop-mediated TRCs. Head-on TRCs can promote R-loop formation followed by the build-up of positively-supercoiled (+SC) domains between converging transcription- and replication machineries, which will cause replication fork stalling. Stalled replication forks are protected by the RAD51 filament, which can promote fork reversal by DNA translocase ZRANB3. Fork reversal is counteracted by RECQ1 helicase. RECQ5 helicase disrupts the RAD51 filament to prevent fork reversal and to facilitate fork cleavage by MUS81 endonuclease, which releases the topological barrier in the DNA template and triggers reactivation of transcription by ELL. After fork religation by RAD52 and LIG4/XRCC4, the reactivated transcription complex can bypass the replication-stalling site and continue RNA synthesis on the lagging arm of the fork. This is followed by replisome reloading and restart of DNA synthesis. It is assumed that after fork stalling, the replicative helicase CMG traverses the fork junction onto dsDNA via its ssDNA gate [59]. After fork religation, CMG translocates back onto ssDNA to allow the passage of the transcription complex and to nucleate a functional replisome. (B) TRC resolution mediated by RECQ5-dependent PCNA SUMOylation. Interaction of RNAPIIo-bound RECQ5 with PCNA triggers the PCNA SUMO2 conjugation. SUMO2-PCNA enriches histone chaperones CAF1 and FACT at replication forks to deposit repressive histones, causing RNAPII dissociation.