Table 1.
R-loop resolution and suppression factors and their links to disease. Bold denotes a gain-of-function mutation for that factor associated with disease, while italics signifies a loss-of-function mutation.
| Gene | Description | Disease | Reference |
|---|---|---|---|
| ADAR1 | Edits mismatches to promote RNase H2 R-loop resolution | Telomerase-Reactivated Cancers | (Shiromoto et al., 2021) |
| BRCA1 | Suppresses satellite RNA production to suppress R-loops; also sequestered by satellite RNAs preventing its proper functioning | Breast and Ovarian Cancers | (Zhu et al., 2018) |
| Resolves R-loops at transcription termination sites (with SETX) | (Hatchi et al., 2015) | ||
| Limits RNAPII proximal pausing, preventing instability | (Zhang et al., 2017) | ||
| Limits the ESR1 R-loop to maintain neighboring gene transcription | (Chiang et al., 2019) | ||
| BRCA2 | Resolves R-loops and limits genomic instability | Breast and Ovarian Cancer | (Bhatia et al., 2014) |
| Depletion by aldehydes increases replication stress and instability | (Tan et al., 2017) | ||
| Promotes the transition of RNAPII from an initiating to an elongating complex | (Shivji et al., 2018) | ||
| C9orf72 | R-loops formed over this region interfere with transcription and promote disease pathologies | ALS/Frontotempor al Dementia (FTD) | (Haeusler et al., 2014; Reddy et al., 2014) |
| CDCA7/HELLS | Promotes methylation at pericentromeres to suppress R-loops | ICF Syndrome | (Unoki et al., 2020) |
| CSB | Processes R-loops to limit levels | Cockayne Syndrome (CS) | (Sollier et al., 2014) |
| Dicer | Prevents R-loop associated genome instability | Embryonal Tumors with Multilayered Rosettes (ETMR) | (Lambo et al., 2019) |
| DDX41 | Recognizes viral hybrids to initiate immune signaling | Human Immunodeficiency Virus (HIV) | (Stavrou et al., 2018) |
| Regulates alternative splicing | Cervical Cancer | (Qin et al., 2021) | |
| Suppresses R-loops and R-loop-induced immune signaling | Myelodysplastic Syndromes | (Weinreb et al., 2021) | |
| Estrogen | Induces transcription and R-loops, leading to instability | Breast/Ovarian Cancer | (Stork et al., 2016) |
| EWS-FLI | Promotes R-loop formation and prevents BRCA1 localization to damage sites | Ewing’s Sarcoma | (Gorthi et al., 2018) |
| FANCM FANCD2 |
Resolves TERRA R-loops to limit genome instability and regulate ALT activity | ALT cancers | (Pan et al., 2019; Silva et al., 2019) |
| Suppresses R-loops and TRCs to maintain genomic stability | Fanconi Anemia | (García-Rubio et al., 2015; Schwab et al., 2015) | |
| FXN FMR1 |
R-loops in these genes lead to transcriptional silencing | Fragile X Syndrome Friedreich Ataxia | (Colak et al., 2014; Groh et al., 2014; Loomis et al., 2014) |
| H. pylori | Activates Nf-kB-driven expression, leading to TRCs and damage | Gastric Cancer | (Bauer et al., 2020) |
| HRAS | Increases RNA synthesis and R-loops leading to increased damage and replication stress | Many Cancers | (Kotsantis et al., 2016) |
| INO80 | Remodels chromatin to suppress R-loops and prevent TRCs | Multiple Cancers | (Prendergast et al., 2020) |
| MDM2/RNF2 | Ubiquitinates H2A to increase replication and prevent R-loops | Sarcomas | (Klusmann et al., 2018) |
| MYCN | MYCN recruits BRCA1 to release RNAPII from proximal pause to prevent R-loops | Neuronal and Neuroendocrine Cancers (eg. Neuroblastoma) | (Herold et al., 2019) |
| RECQ4 | Resolves mitochondrial R-loops to promote mtDNA replication | Rothmund-Thomson Syndrome, RAPADILINO, Baller-Gerold Syndrome | (Chang et al., 2020) |
| RNase H2 | Suppress R-loop formation and genomic instability | Aicardi-Goutières Syndrome (AGS) | (Giordano et al., 2022; Mackenzie et al., 2016) |
| SAMHD1 | Suppress R-loop accumulation and R-loop induced TRCs | AGS | (Lim et al., 2015; Park et al., 2021) |
| SAN1 | Interacts with SETX to resolve R-loops | Cardiomyopathies | (Liu et al., 2021c) |
| SETX | Resolves R-loops to prevent instability | AOA2 | (Becherel et al., 2015) |
| Resolves R-loops to prevent aberrant TGF-β signaling | Amyotrophic Lateral Sclerosis (ALS4) | (Grunseich et al., 2018) | |
| Interacts with ZPR1 to resolve R-loops | Amyotrophic Lateral Sclerosis (ALS4) | (Kannan et al., 2022) | |
| Promotes meiosis | Infertility | (Becherel et al., 2013) | |
| SF3B1 U2AF1 SRSF2 |
Maintain splicing to prevent R-loops | Myelodysplastic Syndromes | (Cheruiyot et al., 2021; Sorrells et al., 2018) |
| Promotes RNAPII release from promoter pause sites | (Chen et al., 2018) | ||
| When lost, R-loops activate ATR to promote survival | (Nguyen et al., 2018) | ||
| SMN1 | Promotes splicing to prevent R-loops and instability | SMA | (Jangi et al., 2017) |
| Snord116 | Loss of R-loops in this region leads to altered imprinting and chromatin condensation | Prader-Willi Syndrome | (Powell et al., 2013) |
| SS18-SSX | Increases R-loop formation | Synovial Sarcoma | (Jones et al., 2017) |
| TDP-43 | Suppress hybrid formation and replication stress | ALS/FTD | (Giannini et al., 2020; Wood et al., 2020) |
| TDRD3/TOP3B | Induces negative supercoiling and increases R-loop resolution via DHX9 to prevent c-MYC/IgH translocations | Multiple Myeloma Burkhitt’s Lymphoma | (Yang et al., 2014; Yuan et al., 2021) |
| TERRA | DNMT3B mutations in ICF cells elevate TERRA, increasing R-loops and causing telomere shortening | Immunodeficiency, Centromere instability and facial anomalies syndrome (ICF) | (Sagie et al., 2017) |
| Increased production leads to increased R-loops and recombination to lengthen telomeres, mediated by RNase H1 | Alternative-Lengthening of Telomeres (ALT)-driven cancers | (Arora et al., 2014) | |
| TonEBP | Recruits METTL3 to resolve R-loops and maintain stability | Hepatocellular carcinoma | (Kang et al., 2021; Ye et al., 2021) |
| TPR | Prevents R-loop formation and maintains fork progression | Ovarian cancers Others | (Kosar et al., 2021) |
| TREX (Transcription-export) complex | Prevents R-loop formation and DNA breaks; sequestered and inhibited by KSHV ORF57 | Kaposi’s Sarcoma | (Jackson et al., 2014) |
| TREX1 | Suppress R-loop formation and maintain genome stability; maintain DNA methylation | AGS | (Giordano et al., 2022; Lim et al., 2015) |
| XPF | Processes R-loops to limit levels | XP | (Cristini et al., 2019; Goulielmaki et al., 2021; Makharashvili et al., 2018; Sollier et al., 2014) |
| Processes R-loops to limit cytosolic ssDNA accumulation and inflammation | Chronic Pancreatitis | (Chatzidoukaki et al., 2021) | |
| XPG | Processes R-loops to limit their levels | Xeroderma Pigmentosum (XP) | (Cristini et al., 2019; Goulielmaki et al., 2021; Makharashvili et al., 2018; Sollier et al., 2014). |
| ZPR1 | Interacts with SETX to resolve R-loops | ALS4 | (Kannan et al., 2022) |
| Regulates SETX and SMN2 levels to promote R-loop resolution | Spinal Muscular Atrophy (SMA) | (Kannan et al., 2020, 2022) |