Table 1.
R-loops and links to human disease.
| Disease | R-loop factor/locus | Proposed mechanism | References |
|---|---|---|---|
| Breast/Ovarian | Estrogen | Estrogen-induced R-loops cause DNA damage and genome instability. | Stork et al., 2016 |
| BRCA1 | BRCA1 interacts with SETX and suppresses R-loops and DNA breaks at gene terminators. | Hatchi et al., 2015 | |
| RNAP II pausing contributes to BRCA1-associated R-loop accumulation and breast cancer development. | Zhang et al., 2017 | ||
| BRCA1 is sequestered in cells expressing heterochromatin-associated noncoding RNAs, leading to genome instability. | Zhu et al., 2018 | ||
| BRCA2 | BRCA2 depletion elevates R-loop levels and causes genome instability. | Bhatia et al., 2014 | |
| Aldehydes deplete BRCA2 and cause R-loop-dependent genome instability. | Tan et al., 2017 | ||
| BRCA2 depletion causes transcription stress at gene promoters and R-loop-mediated DNA damage. | Shivji et al., 2018 | ||
| Ewing Sarcoma | EWS-FLI, BRCA1 | R-loops cause transcriptional stress, resulting in functional depletion of BRCA1 and subsequent DNA damage. | Gorthi et al., 2018 |
| Myelodysplastic syndromes (MDS) | SRSF2, U2AF1 | R-loops induced by splicing factor mutations cause replication stress and impair bone cell function. | Chen et al., 2018 |
| Multiple myeloma and Burkhitt’s lymphoma | TRD3-TOP3B | TRD3-TOP3B complex relieves negative supercoiling and reduces R-loop levels at c-MYC and Igh to suppress chromosomal translocations. | Yang et al., 2014 |
| Alternative lengthening of telomeres (ALT)-dependent cancers | Telomeric repeat-containing RNA (TERRA) | TERRA R-loops are upregulated in cancer cells and promote homologous recombination to preserve telomeres by the ALT pathway. | Arora et al., 2014 |
| Fanconi Anemia (FA) | FANCM, FANCD2 | FA factor deficiency leads to increased R-loop levels, exacerbating TRCs and causing genome instability. | Schwab et al., 2015, Garcia-Rubio et al., 2015 |
| AOA2 | SETX | SETX resolves R-loops in neuronal cells; R-loops are elevated in neural progenitor cells from AOA2 patients with SETX mutations. | Becherel et al., 2015 |
| ALS4 | Gain-of-function SETX mutation in ALS4 decreases R-loops levels, increases DNA methylation and upregulates inflammation genes. | Grunseich et al., 2018 | |
| Infertility | SETX | SETX is required for meiosis in mice; SETX−/− mice are infertile and accrue R-loops in germ cells. | Becherel et al., 2013 |
| Prader-Willi Syndrome | SNORD116 | Loss of R-loop formation at the SNORD116 locus in neurons leads to changes in expression of imprinted genes. | Powell et al., 2013 |
| Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) | C9ORF72 (C9) | R-loops form at repeat expansions, causing transcriptional interference and abortive transcripts, which sequester proteins and cause cellular stress. Alternatively, R-loop processing causes repeat instability. | Haeusler et al., 2014, Reddy et al., 2014 |
| Friedreich ataxia (FRDA) and Fragile X syndrome (FXS) | FXN, FMR1 | R-loops forming at repeat expansions impede RNAPII, causing gene silencing and promoting heterochromatin formation. | Groh et al., 2014 Colak et al., 2014, Loomis et al., 2014 |
| Aicardi Goutieres Syndrome (AGS) | RNaseH2, SAMHD1, TREX1 | Elevated R-loops are associated with decreased DNA methylation in AGS cells. | Lim et al., 2015 |
| Immunodeficiency, centromere instability and facial anomalies syndrome (ICF) | TERRA | Dysregulation of TERRA-R-loops causes telomere attrition. | Sagie et al., 2017 |
| AIDS-associated malignancies | TREX complex | Kaposi’s sarcoma-associated herpesvirus sequesters the transcription and export factor TREX, elevating R-loops and causing genome instability. | Jackson et al., 2014 |