International Journal of Molecular Sciences (Feb 2021)
A Role for Human DNA Polymerase λ in Alternative Lengthening of Telomeres
- Elisa Mentegari,
- Federica Bertoletti,
- Miroslava Kissova,
- Elisa Zucca,
- Silvia Galli,
- Giulia Tagliavini,
- Anna Garbelli,
- Antonio Maffia,
- Silvia Bione,
- Elena Ferrari,
- Fabrizio d’Adda di Fagagna,
- Sofia Francia,
- Simone Sabbioneda,
- Liuh-Yow Chen,
- Joachim Lingner,
- Valerie Bergoglio,
- Jean-Sébastien Hoffmann,
- Ulrich Hübscher,
- Emmanuele Crespan,
- Giovanni Maga
Affiliations
- Elisa Mentegari
- Institute of Molecular Genetics IGM-CNR “Luigi Luca Cavalli-Sforza”, via Abbiategrasso 207, 27100 Pavia, Italy
- Federica Bertoletti
- Institute of Molecular Genetics IGM-CNR “Luigi Luca Cavalli-Sforza”, via Abbiategrasso 207, 27100 Pavia, Italy
- Miroslava Kissova
- Institute of Molecular Genetics IGM-CNR “Luigi Luca Cavalli-Sforza”, via Abbiategrasso 207, 27100 Pavia, Italy
- Elisa Zucca
- Institute of Molecular Genetics IGM-CNR “Luigi Luca Cavalli-Sforza”, via Abbiategrasso 207, 27100 Pavia, Italy
- Silvia Galli
- Institute of Molecular Genetics IGM-CNR “Luigi Luca Cavalli-Sforza”, via Abbiategrasso 207, 27100 Pavia, Italy
- Giulia Tagliavini
- Institute of Molecular Genetics IGM-CNR “Luigi Luca Cavalli-Sforza”, via Abbiategrasso 207, 27100 Pavia, Italy
- Anna Garbelli
- Institute of Molecular Genetics IGM-CNR “Luigi Luca Cavalli-Sforza”, via Abbiategrasso 207, 27100 Pavia, Italy
- Antonio Maffia
- Institute of Molecular Genetics IGM-CNR “Luigi Luca Cavalli-Sforza”, via Abbiategrasso 207, 27100 Pavia, Italy
- Silvia Bione
- Institute of Molecular Genetics IGM-CNR “Luigi Luca Cavalli-Sforza”, via Abbiategrasso 207, 27100 Pavia, Italy
- Elena Ferrari
- Department of Molecular Mechanisms of Disease, University of Zürich-Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland
- Fabrizio d’Adda di Fagagna
- Institute of Molecular Genetics IGM-CNR “Luigi Luca Cavalli-Sforza”, via Abbiategrasso 207, 27100 Pavia, Italy
- Sofia Francia
- Institute of Molecular Genetics IGM-CNR “Luigi Luca Cavalli-Sforza”, via Abbiategrasso 207, 27100 Pavia, Italy
- Simone Sabbioneda
- Institute of Molecular Genetics IGM-CNR “Luigi Luca Cavalli-Sforza”, via Abbiategrasso 207, 27100 Pavia, Italy
- Liuh-Yow Chen
- Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Frontiers in Genetics National Center of Competence in Research, Ecole Polytechnique Fédérale de Lausanne (EPFL), Station 19, CH-1015 Lausanne, Switzerland
- Joachim Lingner
- Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Frontiers in Genetics National Center of Competence in Research, Ecole Polytechnique Fédérale de Lausanne (EPFL), Station 19, CH-1015 Lausanne, Switzerland
- Valerie Bergoglio
- UMR1037 INSERM, Cancer Research Center of Toulouse, 2 Avenue Curien, 31037 Toulouse, France
- Jean-Sébastien Hoffmann
- Laboratoire d’Excellence Toulouse Cancer (TOUCAN), Laboratoire de Pathologie, Institut Universitaire du Cancer-Toulouse, Oncopole, 1 Avenue Irène-Joliot-Curie, 31059 Toulouse, France
- Ulrich Hübscher
- Department of Molecular Mechanisms of Disease, University of Zürich-Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland
- Emmanuele Crespan
- Institute of Molecular Genetics IGM-CNR “Luigi Luca Cavalli-Sforza”, via Abbiategrasso 207, 27100 Pavia, Italy
- Giovanni Maga
- Institute of Molecular Genetics IGM-CNR “Luigi Luca Cavalli-Sforza”, via Abbiategrasso 207, 27100 Pavia, Italy
- DOI
- https://doi.org/10.3390/ijms22052365
- Journal volume & issue
-
Vol. 22,
no. 5
p. 2365
Abstract
Telomerase negative cancer cell types use the Alternative Lengthening of Telomeres (ALT) pathway to elongate telomeres ends. Here, we show that silencing human DNA polymerase (Pol λ) in ALT cells represses ALT activity and induces telomeric stress. In addition, replication stress in the absence of Pol λ, strongly affects the survival of ALT cells. In vitro, Pol λ can promote annealing of even a single G-rich telomeric repeat to its complementary strand and use it to prime DNA synthesis. The noncoding telomeric repeat containing RNA TERRA and replication protein A negatively regulate this activity, while the Protection of Telomeres protein 1 (POT1)/TPP1 heterodimer stimulates Pol λ. Pol λ associates with telomeres and colocalizes with TPP1 in cells. In summary, our data suggest a role of Pol λ in the maintenance of telomeres by the ALT mechanism.
Keywords
- alternative lengthening of telomeres (ALT)
- DNA polymerase λ
- DNA double-strand breaks (DSBs)
- extra-chromosomal telomeric repeats (ECTRs)
- promyelocytic leukemia (PML) bodies
- telomere dysfunction-induced foci (TIFs)
