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Article

A Role for Human DNA Polymerase λ in Alternative Lengthening of Telomeres

1
Institute of Molecular Genetics IGM-CNR “Luigi Luca Cavalli-Sforza”, via Abbiategrasso 207, 27100 Pavia, Italy
2
Department of Molecular Mechanisms of Disease, University of Zürich-Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland
3
IFOM-The FIRC Institute of Molecular Oncology, 20139 Milan, Italy
4
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
5
UMR1037 INSERM, Cancer Research Center of Toulouse, 2 Avenue Curien, 31037 Toulouse, France
6
Laboratoire d’Excellence Toulouse Cancer (TOUCAN), Laboratoire de Pathologie, Institut Universitaire du Cancer-Toulouse, Oncopole, 1 Avenue Irène-Joliot-Curie, 31059 Toulouse, France
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Present address: Institute of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Erling Skjalgssons gt 1, 7491 Trondheim, Norway.
§
These authors should be considered joint senior authors.
Academic Editor: Irmgard Tegeder
Int. J. Mol. Sci. 2021, 22(5), 2365; https://doi.org/10.3390/ijms22052365
Received: 20 January 2021 / Revised: 13 February 2021 / Accepted: 23 February 2021 / Published: 27 February 2021
(This article belongs to the Collection Feature Papers in Molecular Biology)
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. View Full-Text
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); telomere stress; microhomology-mediated strand transfer (MMST) activity 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); telomere stress; microhomology-mediated strand transfer (MMST) activity
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MDPI and ACS Style

Mentegari, E.; Bertoletti, F.; Kissova, M.; Zucca, E.; Galli, S.; Tagliavini, G.; Garbelli, A.; Maffia, A.; Bione, S.; Ferrari, E.; d’Adda di Fagagna, F.; Francia, S.; Sabbioneda, S.; Chen, L.-Y.; Lingner, J.; Bergoglio, V.; Hoffmann, J.-S.; Hübscher, U.; Crespan, E.; Maga, G. A Role for Human DNA Polymerase λ in Alternative Lengthening of Telomeres. Int. J. Mol. Sci. 2021, 22, 2365. https://doi.org/10.3390/ijms22052365

AMA Style

Mentegari E, Bertoletti F, Kissova M, Zucca E, Galli S, Tagliavini G, Garbelli A, Maffia A, Bione S, Ferrari E, d’Adda di Fagagna F, Francia S, Sabbioneda S, Chen L-Y, Lingner J, Bergoglio V, Hoffmann J-S, Hübscher U, Crespan E, Maga G. A Role for Human DNA Polymerase λ in Alternative Lengthening of Telomeres. International Journal of Molecular Sciences. 2021; 22(5):2365. https://doi.org/10.3390/ijms22052365

Chicago/Turabian Style

Mentegari, Elisa, 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, and Giovanni Maga. 2021. "A Role for Human DNA Polymerase λ in Alternative Lengthening of Telomeres" International Journal of Molecular Sciences 22, no. 5: 2365. https://doi.org/10.3390/ijms22052365

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