Table 1.
Cancer relevant genes linked with R-loops
| Genes | Details/remarks | References |
|---|---|---|
| SRSF2, U2AF1, SF3B1, U2AF2, and ZRSR2 |
Mutations in these splicing factors cause pausing of POL2, increased R-loops, replication stress and genomic instability Linked with myelodysplastic syndromes (MDSs), acute myeloid leukemia (AML), uveal melanoma, bladder, pancreatic and lung cancer |
(96–98,100,162–170) |
| BRCA1 | BRCA1 regulates transcription elongation and its inactivation induces R-loops at the 5′ end of genes with promoter-proximal POL2 pausing (by counteracting its binding partner COBRA1), transcription and R-loops at 3′ transcription termination pause sites (with senataxin), R-loops at centromeric α-satellite repeats, telomeric TERRA R-loops Luminal progenitor cells of BRCA1-associated breast tumors accumulate R-loops Ewing sarcoma phenocopies BRCA1-deficient tumors. BRCA1 sequestration by transcription machinery and R-loop structures causes HR defect In MYCN-amplified human neuroblastoma cells, BRCA1 limits MYCN driven R-loop formation in promoter-proximal regions |
(54,171–177) |
| BRCA2 | Interacts with POL2 and regulates R-loops formed at promoter-proximal pause sites at the 5′ end of genes Associates with TREX-2 to prevent R-loop accumulation Regulates DNA-RNA hybrid level at DSBs by recruiting RNase H2 Associates with and promotes DDX5 activity to control R-loops at DSBs |
(93,121,178–180) |
| FANCA, FANCD2, FANACI, FANCJ, and FANCM | Reduce R-loops at transcription–replication conflict regions In FANCD2-/- patient-derived lymphoblast R-loops cause replication fork arrest at common fragile site (CFS) |
(181–184) |
| EWS–FLI1 | Fusion of N-terminal of EWSR1 and C-terminal of FLI1 protein. Regulates R-loops by controlling POL2 elongation step and via interaction with splicing machinery |
(175) |
| TOP3B | TOP3B deletion is linked increased accumulation of R-loops in renal cancer cells from patient | (75) |
| ATRX (alpha thalassemia/mental retardation X-linked) | Mutated in ALT-positive human tumors (brain cancers, pancreatic neuroendocrine tumors, chondroblastomas, and osteosarcomas) and implicated in alternative lengthening of telomeres activation Chromatin remodeling factor; Controls R-loops in telomeres and rDNA repeats. Interacts with RNAs and prevent DNA-RNA hybrid formation in R-loops |
(185–188) |
| RecQ helicases |
BLM possibly unwinds DNA-RNA hybrid of R-loops and protects cells from genome instability WRN plays role in activation of ATR/CHK1, and ATM signaling pathways and protect cells from R-loop induced genome instability |
(124,125,189–191) |
| SS18–SSX1 oncoprotein |
Fusion of the SS18 subunit of BAF chromatin remodeling complex with SSX Promotes R-loops and replication stress in synovial sarcoma |
(192) |
| HRAS | Increases global transcription and R-loop formation | (193) |