Table 2 R-loop and Links to Human Disease
Disease | R-loop factors | Suggested mechanism | References |
|---|---|---|---|
Ovarian cancer | ADAR1 | Silence of ADAR1 repressed ovarian cancer cell growth and caused R-loop abnormal accumulation. | [70] |
Breast and ovarian cancers | BRCA1 BRCA2 | The mutations or deletions of BRCA1 and BRCA2 can lead to increased R-loop levels and DNA damage. | |
Aicardi-Goutières syndrome (AGS) | TREX1 RNase H2 SAMHD1 | Mutations in TREX1, RNASEH2A, RNASEH2B, and SAMHD1 are associated with the accumulation of RNA: DNA hybrids over repeat-rich intergenic and gene body regions. | [139] |
R-loops are highly enriched at transcription-replication conflict regions of the genome in fibroblast patients bearing SAMHD1 mutation. | [68] | ||
Type 4 amyotrophic lateral sclerosis (ALS4) | SETX ZPR1 | ZPR1-deficiency causes downregulation of SETX and accumulation of R-loops. | [140] |
Amyotrophic lateral sclerosis (ALS) | TDP-43 | Mutated TDP-43 in transfected neuronal SH-SY5Y and lymphoblastoid cell lines (LCLs) from an ALS patient cause R-loop accumulation. | [141] |
Ataxia with oculomotor apraxia 2 (AOA-2) | SETX | SETX can resolve the R-loop in AOA2 iPSCs. | [142] |
Hepatocellular carcinoma (HCC) | THOC1 MTA2 TonEBP | Knockdown of THOC1 leads to R-loop formation, and DNA damage and confers sensitivity to cisplatin. | |
MTA2 could interact with HDAC2/CHD4, and transcriptionally inhibit BDH1 by R-loop, leading to HCC formation and progression. | |||
TonEBP prevents R-loop-mediated DNA damage in HepG2 human hepatoma cells. | |||
Testicular seminoma (TS) | BRE1 | Aberrant R-loop constitutes a significant source of DSBs in BRE1-deficient cells. | [146] |
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) | C9orf72 | C9orf72 repeat expansion can induce DNA damage response leading to ALS/FTD pathologies. | [147] |
Friedreich ataxia (FRDA) and fragile X syndrome (FXS) | FXN FMR1 | R-loop acts as an initial trigger to promote FXN and FMR1 silencing. | [148] |
Xeroderma pigmentosum (XP) | XPF XPG | Processes R-loops to limit their levels. | |
Kaposi’s Sarcoma (KS) | THO/TREX complex | THO/TREX prevents the formation of R-loop that can compromise genome integrity. | [115] |
Fanconi anemia (FA) | FANCM FANCD2 | Suppresses R-loop and prevents R-loop-dependent DNA damage. | [58] |
Spinal muscular atrophy (SMA) | SMN1 ZPR1 | ZPR1 rescues defective RLRC assembly and prevents pathogenic R-loop accumulation in SMA. | [140] |
Multiple cancers | INO80 HRAS | INO80-dependent resolution of R-loop promotes DNA replication. | |
Mutated HRAS activation causes aberrant replication fork acceleration and DNA damage by decreasing the R-loop. | |||
Myelodysplastic syndromes (MDS) | DDX41 | DDX41 suppression of R-loop levels and inflammatory signaling. | [150] |
Immunodeficiency, centromere instability, and facial anomalies syndrome (ICF) | TERRA | RNA: DNA hybrids promote damage and instability at telomeric regions in ICF. | [151] |