Figure 1.

Potential modes of action for DNA damage proteins in R-loop mitigation. (A) R-loop structure is shown (RNA = red; DNA = grey/black) occurring co-transcriptionally with RNA polymerase (RNAP). The RNA exits RNAPII at a separate position from the template DNA so the RNA must re-invade to form an R-loop. Also shown are core anti-R-loop enzymatic activities: RNase H which degrades the RNA moiety; Helicases such as Senataxin (Sen1)³⁹ or Aquarius (AQR)²⁵ which may unwind R-loops; and Topoisomerase which reduces topological strain favoring RNA invasion. (B) DNA damage induced R-loops. Transcription into a damaged DNA region would experience altered chromatin environment (i.e. remodelers actively suppress transcription next to breaks²⁰), collision with repair proteins or be subject to orchestrated disassembly by DNA repair signaling (e.g. spliceosome displacement favoring R-loops²¹). (C) Direct processing of R-loops into DNA breaks by the transcription-coupled nucleotide excision repair (TC-NER) machinery. Putative cut sites are shown in yellow although the cut strand is not known²⁵. (D) Interplay between replication fork protection activities and R-loop stability. At sites of transcription-replication conflict the Fanconi Anemia pathway, which includes BRCA1, BRCA2 and XPF, act to suppress R-loop formation^{36; 37}. The FANCM helicase is shown as a mediator that could directly remove R-loops through its strand migration activity³⁶.