Proteomic Profiling Reveals a Specific Role for Translesion DNA Polymerase η in the Alternative Lengthening of Telomeres

Cell Reports

Jean-Sébastien Hoffmann¹  Valérie Bergoglio¹  Elodie Bournique¹  Marietta Lee²  Sufang Zhang²  Callen T. Wallace³  Simon C. Watkins³  Arindam Bose⁴  Patricia L. Opresko⁴  Roderick J. O’Sullivan⁵  Laura Garcia-Exposito⁵  Justin L. Roncaioli⁵  Jonathan Barroso-Gonzalez⁵ 

[1] CRCT, Université de Toulouse, Inserm, CNRS, UPS Equipe Labellisée Ligue Contre le Cancer, Laboratoire d’Excellence Toulouse Cancer, 2 Avenue Hubert Curien, 31037 Toulouse, France;Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA;Department of Cell Biology, University of Pittsburgh Cancer Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA;Department of Environmental and Occupational Health, University of Pittsburgh Cancer Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA;Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA;

关键词: telomere;    BioID;    translesion DNA synthesis;    polymerase;    mitosis;    D-loop;    cancer;   

DOI  :  10.1016/j.celrep.2016.10.048

来源: DOAJ

【 摘 要 】

Cancer cells rely on the activation of telomerase or the alternative lengthening of telomeres (ALT) pathways for telomere maintenance and survival. ALT involves homologous recombination (HR)-dependent exchange and/or HR-associated synthesis of telomeric DNA. Utilizing proximity-dependent biotinylation (BioID), we sought to determine the proteome of telomeres in cancer cells that employ these distinct telomere elongation mechanisms. Our analysis reveals that multiple DNA repair networks converge at ALT telomeres. These include the specialized translesion DNA synthesis (TLS) proteins FANCJ-RAD18-PCNA and, most notably, DNA polymerase eta (Polη). We observe that the depletion of Polη leads to increased ALT activity and late DNA polymerase δ (Polδ)-dependent synthesis of telomeric DNA in mitosis. We propose that Polη fulfills an important role in managing replicative stress at ALT telomeres, maintaining telomere recombination at tolerable levels and stimulating DNA synthesis by Polδ.

【 授权许可】

Unknown