CDK-mediated Yku80 phosphorylation regulates the balance between non-homologous end joining (NHEJ) and homologous directed recombination (HDR)
Autor/a
Carballar, Reyes
Martínez-Láinez, Joan M.
Samper, Bàrbara
Bru, Samuel
Bállega, Elisabet
Mirallas, Oriol
Ricco, Natalia
Jiménez, Javier
Fecha de publicación
2020ISSN
0022-2836
Resumen
There are two major pathways for repairing DNA double-strand breaks (DSBs): homologous directed recombination (HDR) and non-homologous end-joining (NHEJ). While NHEJ functions throughout the cell cycle, HDR is only possible during S/G2 phases, suggesting that there are cell cycle-specific mechanisms regulating the balance between the two repair systems. The regulation exerted by CDKs on HDR has been extensively demonstrated, and here we present evidence that the CDK Pho85, in association with the G1 cyclin Pcl1, phosphorylates Yku80 on Ser 623 to regulate NHEJ activity. Cells bearing a non-phosphorylatable version of Yku80 show increased NHEJ and reduced HDR activity. Accordingly, yku80S623A cells present diminished viability upon treatment with the DSB-producer bleomycin, specifically in the G2 phase of the cell cycle. Interestingly, the mutation of the equivalent residue in human Ku80 increases sensitivity to bleomycin in several cancer cell lines, suggesting that this mechanism is conserved in humans. Altogether, our results reveal a new mechanism whereby G1-CDKs mediate the choice between HDR and NHEJ repair pathways, putting the error prone NHEJ on a leash and enabling error free HDR in G2 when homologous sequences are available.
Tipo de documento
Artículo
Versión del documento
Versión publicada
Lengua
English
Materias (CDU)
61 - Medicina
Palabras clave
ADN
DNA
Páginas
21
Publicado por
Elsevier
Colección
432; 24
Publicado en
Journal of Molecular Biology
Citación
Carballar, Reyes; Martínez-Láinez, Joan M.; Samper, Bàrbara [et al.]. CDK-mediated Yku80 phosphorylation regulates the balance between non-homologous end joining (NHEJ) and homologous directed recombination (HDR). Journal of Molecular Biology, 2020, 432(24), 166715. Disponible en: <https://www.sciencedirect.com/science/article/abs/pii/S0022283620306331?via%3Dihub>. Fecha de acceso: 23 ene. 2024. DOI: 10.1016/j.jmb.2020.11.014
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Derechos
© 2020 Elsevier Ltd. All rights reserved.