| First Author | Mateos-Gomez PA | Year | 2017 |
| Journal | Nat Struct Mol Biol | Volume | 24 |
| Issue | 12 | Pages | 1116-1123 |
| PubMed ID | 29058711 | Mgi Jnum | J:340661 |
| Mgi Id | MGI:6869820 | Doi | 10.1038/nsmb.3494 |
| Citation | Mateos-Gomez PA, et al. (2017) The helicase domain of Poltheta counteracts RPA to promote alt-NHEJ. Nat Struct Mol Biol 24(12):1116-1123 |
| abstractText | Mammalian polymerase theta (Poltheta) is a multifunctional enzyme that promotes error-prone DNA repair by alternative nonhomologous end joining (alt-NHEJ). Here we present structure-function analyses that reveal that, in addition to the polymerase domain, Poltheta-helicase activity plays a central role during double-strand break (DSB) repair. Our results show that the helicase domain promotes chromosomal translocations by alt-NHEJ in mouse embryonic stem cells and also suppresses CRISPR-Cas9- mediated gene targeting by homologous recombination (HR). In vitro assays demonstrate that Poltheta-helicase activity facilitates the removal of RPA from resected DSBs to allow their annealing and subsequent joining by alt-NHEJ. Consistent with an antagonistic role for RPA during alt-NHEJ, inhibition of RPA1 enhances end joining and suppresses recombination. Taken together, our results reveal that the balance between HR and alt-NHEJ is controlled by opposing activities of Poltheta and RPA, providing further insight into the regulation of repair-pathway choice in mammalian cells. |
