2. Academic Validation
  3. RAD51AP1 Is an Essential Mediator of Alternative Lengthening of Telomeres

RAD51AP1 Is an Essential Mediator of Alternative Lengthening of Telomeres

  • Mol Cell. 2019 Oct 3;76(1):11-26.e7. doi: 10.1016/j.molcel.2019.06.043.
Jonathan Barroso-González 1,  Laura García-Expósito 1,  Song My Hoang 1,  Michelle L Lynskey 1,  Justin L Roncaioli 1,  Arundhati Ghosh 2,  Callen T Wallace 3,  Marco de Vitis 4,  Mauro Modesti 5,  Kara A Bernstein 2,  Saumendra N Sarkar 2,  Simon C Watkins 3,  Roderick J O'Sullivan 6
Affiliations

Affiliations

  • 1 Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA.
  • 2 Department of Microbiology and Molecular Genetics, UPMC Hillman Cancer Center, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA.
  • 3 Department of Cell Biology, UPMC Hillman Cancer Center, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA.
  • 4 Department of Science, University of Rome "ROMA TRE", 00146 Rome, Italy.
  • 5 Cancer Research Center of Marseille, CNRS UMR7258, Inserm UMR1068, Aix Marseille Université U105; Institut Paoli Calmettes, 27 Boulevard Lei Roure CS30059, 13273 Marseille, Cedex 09, France.
  • 6 Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA. Electronic address: [email protected].
PMID: 31400850 DOI: 10.1016/j.molcel.2019.06.043
Abstract

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.

Keywords

RAD51AP1; SUMOylation; autophagy; cancer; homology-directed repair; telomere.

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