| First Author | Jiang W | Year | 2015 |
| Journal | Mol Cell | Volume | 58 |
| Issue | 1 | Pages | 172-85 |
| PubMed ID | 25818648 | Mgi Jnum | J:220823 |
| Mgi Id | MGI:5636531 | Doi | 10.1016/j.molcel.2015.02.024 |
| Citation | Jiang W, et al. (2015) Differential Phosphorylation of DNA-PKcs Regulates the Interplay between End-Processing and End-Ligation during Nonhomologous End-Joining. Mol Cell 58(1):172-85 |
| abstractText | Nonhomologous end-joining (NHEJ) is a major DNA double-strand break repair pathway that is conserved in eukaryotes. In vertebrates, NHEJ further acquires end-processing capacities (e.g., hairpin opening) in addition to direct end-ligation. The catalytic subunit of DNA-PK (DNA-PKcs) is a vertebrate-specific NHEJ factor that can be autophosphorylated or transphosphorylated by ATM kinase. Using a mouse model expressing a kinase-dead (KD) DNA-PKcs protein, we show that ATM-mediated transphosphorylation of DNA-PKcs regulates end-processing at the level of Artemis recruitment, while strict autophosphorylation of DNA-PKcs is necessary to relieve the physical blockage on end-ligation imposed by the DNA-PKcs protein itself. Accordingly, DNA-PKcs(KD/KD) mice and cells show severe end-ligation defects and p53- and Ku-dependent embryonic lethality, but open hairpin-sealed ends normally in the presence of ATM kinase activity. Together, our findings identify DNA-PKcs as the molecular switch that coordinates end-processing and end-ligation at the DNA ends through differential phosphorylations. |
