RAD51AP1 Is an Essential Mediator of Alternative Lengthening of Telomeres
In: Molecular Cell Molecular Cell, 2019, 76 (1), pp.11-26.e7. ⟨10.1016/j.molcel.2019.06.043⟩ Mol Cell Molecular Cell, 2019, 76 (1), pp.217. ⟨10.1016/j.molcel.2019.08.009⟩ Molecular Cell, Elsevier, 2019, 76 (1), pp.217. ⟨10.1016/j.molcel.2019.08.009⟩ Molecular Cell, Elsevier, 2019, 76 (1), pp.11-26.e7. ⟨10.1016/j.molcel.2019.06.043⟩; (2019-10-01)
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Zugriff:
Alternative Lengthening of Telomeres (ALT) is a homology-directed repair (HDR) mechanism of telomere elongation that controls proliferation in aggressive cancers. We show that the disruption of RAD51-associated protein 1 (RAD51AP1) in ALT+ cancer cells leads to generational telomere shortening. This is due to RAD51AP1’s involvement in RAD51 dependent homologous recombination (HR) and RAD52-POLD3 dependent break induced DNA synthesis. RAD51AP1 KO ALT+ cells exhibit telomere dysfunction and cytosolic telomeric DNA fragments that are sensed by cGAS. Intriguingly, they activate ULK1-ATG7 dependent autophagy as a survival mechanism to mitigate DNA damage and apoptosis. Importantly, RAD51AP1 protein levels are elevated in ALT+ cells due to MMS21 associated SUMOylation. Mutation of a single SUMO-targeted lysine residue perturbs telomere dynamics. These findings indicate that RAD51AP1 is an essential mediator of the ALT mechanism and is co-opted by post-translational mechanisms to maintain telomere length and ensure proliferation of ALT+ cancer cells.
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RAD51AP1 Is an Essential Mediator of Alternative Lengthening of Telomeres
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| Autor/in / Beteiligte Person: | Barroso-González, Jonathan ; García-Expósito, Laura ; Song My Hoang ; Lynskey, Michelle L. ; Roncaioli, Justin L. ; Ghosh, Arundhati ; Wallace, Callen T. ; Marco de Vitis ; Modesti, Mauro ; Bernstein, Kara A. ; Sarkar, Saumendra N. ; Watkins, Simon C. ; O’Sullivan, Roderick J. ; Centre de Recherche en Cancérologie de Marseille (CRCM) ; Aix Marseille Université (AMU)-Institut Paoli-Calmettes ; Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) ; Department of Microbiology and Molecular Genetics [Pittsburgh, PA, États-Unis] ; University of Pittsburgh School of Medicine ; Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE)-UPMC Hillman Cancer Center [Pittsburgh, PA, États-Unis] ; Department of Microbiology and Molecular Genetics [Pittsburgh, PA, USA] ; Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE) ; Royal Melbourne Institute of Technology University (RMIT University) ; Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes ; Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU) |
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| Quelle: | Molecular Cell Molecular Cell, 2019, 76 (1), pp.11-26.e7. ⟨10.1016/j.molcel.2019.06.043⟩ Mol Cell Molecular Cell, 2019, 76 (1), pp.217. ⟨10.1016/j.molcel.2019.08.009⟩ Molecular Cell, Elsevier, 2019, 76 (1), pp.217. ⟨10.1016/j.molcel.2019.08.009⟩ Molecular Cell, Elsevier, 2019, 76 (1), pp.11-26.e7. ⟨10.1016/j.molcel.2019.06.043⟩; (2019-10-01) |
| Veröffentlichung: | HAL CCSD, 2019 |
| Medientyp: | unknown |
| ISSN: | 1097-2765 (print) ; 1097-4164 (print) |
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