p16/INK4a impairs homologous recombination-mediated DNA repair in human papillomavirus-positive head and neck tumors

Date

2014-01-28

Authors

Dok, Rüveyda
Kalev, Peter
Van Limbergen, Ever Jan
Asbagh, Layka Abbasi
Hauben, Esther
Sablina, Anna
Nuyts, Sandra

Director

Publisher

American Association for Cancer Research
Acceso abierto / Sarbide irekia
Artículo / Artikulua
Versión aceptada / Onetsi den bertsioa

Project identifier

Impacto

Abstract

The p16INK4a protein is a principal cyclin-dependent kinase inhibitor that decelerates the cell cycle. Abnormally high levels of p16INK4a are commonly observed in human papillomavirus (HPV)-positive head and neck squamous cell carcinomas (HNSCC). We and others found that p16INK4a overexpression is associated with improved therapy response and survival of patients with HNSCC treated with radiotherapy. However, the functional role of p16INK4a in HNSCC remains unexplored. Our results implicate p16INK4a in regulation of homologous recombination-mediated DNA damage response independently from its role in control of the cell cycle. We found that expression of p16INK4a dramatically affects radiation sensitivity of HNSCC cells. p16INK4a overexpression impairs the recruitment of RAD51 to the site of DNA damage in HPV-positive cells by downregulating of cyclin D1 protein expression. Consistent with the in vitro findings, immunostaining of HNSCC patient samples revealed that high levels p16INK4a expression significantly correlated with decreased cyclin D1 expression. In summary, these findings reveal an unexpected function of p16INK4a in homologous recombination- mediated DNA repair response and imply p16INK4a status as an independent marker to predict response of patients with HNSCC to radiotherapy.

Description

Keywords

INK4A, Cancer, HPV, HR-mediated DNA repair, RAD51

Department

Ciencias / Zientziak

Faculty/School

Degree

Doctorate program

item.page.cita

Dok, R., Kalev, P., Van Limbergen, E. J., Asbagh, L. A., Vázquez, I., Hauben, E., Sablina, A., Nuyts, S. (2014) P16INK4a impairs homologous recombination-mediated DNA repair in human papillomavirus-positive head and neck tumors. Cancer Research, 74(6), 1739-1751. https://doi.org/10.1158/0008-5472.CAN-13-2479

item.page.rights

© 2014 American Association for Cancer Research. This Accepted Manuscript is licensed under a Creative Commons Attribution 4.0 International License.

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