| First Author | Ghezraoui H | Year | 2018 |
| Journal | Nature | Volume | 560 |
| Issue | 7716 | Pages | 122-127 |
| PubMed ID | 30046110 | Mgi Jnum | J:265292 |
| Mgi Id | MGI:6199088 | Doi | 10.1038/s41586-018-0362-1 |
| Citation | Ghezraoui H, et al. (2018) 53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ. Nature 560(7716):122-127 |
| abstractText | 53BP1 governs a specialized, context-specific branch of the classical non-homologous end joining DNA double-strand break repair pathway. Mice lacking 53bp1 (also known as Trp53bp1) are immunodeficient owing to a complete loss of immunoglobulin class-switch recombination(1,2), and reduced fidelity of long-range V(D)J recombination(3). The 53BP1-dependent pathway is also responsible for pathological joining events at dysfunctional telomeres(4), and its unrestricted activity in Brca1-deficient cellular and tumour models causes genomic instability and oncogenesis(5-7). Cells that lack core non-homologous end joining proteins are profoundly radiosensitive(8), unlike 53BP1-deficient cells(9,10), which suggests that 53BP1 and its co-factors act on specific DNA substrates. Here we show that 53BP1 cooperates with its downstream effector protein REV7 to promote non-homologous end joining during class-switch recombination, but REV7 is not required for 53BP1-dependent V(D)J recombination. We identify shieldin-a four-subunit putative single-stranded DNA-binding complex comprising REV7, c20orf196 (SHLD1), FAM35A (SHLD2) and FLJ26957 (SHLD3)-as the factor that explains this specificity. Shieldin is essential for REV7-dependent DNA end-protection and non-homologous end joining during class-switch recombination, and supports toxic non-homologous end joining in Brca1-deficient cells, yet is dispensable for REV7-dependent interstrand cross-link repair. The 53BP1 pathway therefore comprises distinct double-strand break repair activities within chromatin and single-stranded DNA compartments, which explains both the immunological differences between 53bp1- and Rev7- deficient mice and the context specificity of the pathway. |
