Fig. 4 |. Roles of the Brca1 complex in protecting regressed replication forks and resolving r-loops.

a | During DNA replication, when the DNA polymerase ensemble comprising DNA polymerase-ε (Polε), PCNA and the CDC45-MCM-GINS (CMG) helicase complex on the leading strand and Polδ-PCNA on the lagging strand is impeded by a DNA structure or lesion, one of the nucleic acid motor proteins SMARCAL1, HLTF or ZRANB3 can catalyse the reversal of the replication fork, a process often referred to as ‘replication fork regression’, to generate a four-armed DNA structure that harbours a free DNA end. Formation of the regressed fork allows a replicative mechanism of lesion bypass^15,227. However, the free DNA end is prone to attack by MRE11 and other nucleases in conjunction with the PTIP complex¹⁴⁸, unless RAD51 is deposited on the regressed fork. The stability of the regressed fork is also dependent on breast cancer type 1 susceptibility protein (BRCA1)-BRCA1-associated RING domain 1 (BARD1), BRCA2 and biorientation of chromosomes in cell division protein 1-like 1 (BOD1L), which are postulated to stabilize the RAD51-DNA interaction to prevent nucleolytic attrition^139,140,146. Other pathways of replication fork repair and restart have been identified, and readers are referred to several comprehensive reviews on this topic^227–229. b | Stalling of RNA polymerase II (Pol II) or delay in mRNA processing can lead to accumulation of R-loops (RNA-DNA hybrids). An R-loop can stall the DNA replication machinery, thereby causing fork collapse and the formation of a DNA double-strand break (DSB). BRCA1-BARD1 and the putative RNA-DNA helicase senataxin (SETX) facilitate R-loop resolution¹⁵⁵.