Proteomic Profiling Reveals a Specific Role for Translesion DNA Polymerase η in the Alternative Lengthening of Telomeres
Laura Garcia-Exposito,
Elodie Bournique,
Valérie Bergoglio,
Arindam Bose,
Jonathan Barroso-Gonzalez,
Sufang Zhang,
Justin L. Roncaioli,
Marietta Lee,
Callen T. Wallace,
Simon C. Watkins,
Patricia L. Opresko,
Jean-Sébastien Hoffmann,
Roderick J. O’Sullivan
Affiliations
Laura Garcia-Exposito
Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Elodie Bournique
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
Valérie Bergoglio
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
Arindam Bose
Department of Environmental and Occupational Health, University of Pittsburgh Cancer Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Jonathan Barroso-Gonzalez
Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Sufang Zhang
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA
Justin L. Roncaioli
Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Marietta Lee
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA
Callen T. Wallace
Department of Cell Biology, University of Pittsburgh Cancer Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Simon C. Watkins
Department of Cell Biology, University of Pittsburgh Cancer Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Patricia L. Opresko
Department of Environmental and Occupational Health, University of Pittsburgh Cancer Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Jean-Sébastien Hoffmann
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
Roderick J. O’Sullivan
Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
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.
