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 |