| First Author | Zhang B | Year | 2023 |
| Journal | Nucleic Acids Res | Volume | 51 |
| Issue | 21 | Pages | 11668-11687 |
| PubMed ID | 37831098 | Mgi Jnum | J:343314 |
| Mgi Id | MGI:7563475 | Doi | 10.1093/nar/gkad839 |
| Citation | Zhang B, et al. (2023) ADAR1 links R-loop homeostasis to ATR activation in replication stress response. Nucleic Acids Res 51(21):11668-11687 |
| abstractText | Unscheduled R-loops are a major source of replication stress and DNA damage. R-loop-induced replication defects are sensed and suppressed by ATR kinase, whereas it is not known whether R-loop itself is actively involved in ATR activation and, if so, how this is achieved. Here, we report that the nuclear form of RNA-editing enzyme ADAR1 promotes ATR activation and resolves genome-wide R-loops, a process that requires its double-stranded RNA-binding domains. Mechanistically, ADAR1 interacts with TOPBP1 and facilitates its loading on perturbed replication forks by enhancing the association of TOPBP1 with RAD9 of the 9-1-1 complex. When replication is inhibited, DNA-RNA hybrid competes with TOPBP1 for ADAR1 binding to promote the translocation of ADAR1 from damaged fork to accumulate at R-loop region. There, ADAR1 recruits RNA helicases DHX9 and DDX21 to unwind R-loops, simultaneously allowing TOPBP1 to stimulate ATR more efficiently. Collectively, we propose that the tempo-spatially regulated assembly of ADAR1-nucleated protein complexes link R-loop clearance and ATR activation, while R-loops crosstalk with blocked replication forks by transposing ADAR1 to finetune ATR activity and safeguard the genome. |
