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Mol Cell. 2019 Aug 7. pii: S1097-2765(19)30500-3. doi: 10.1016/j.molcel.2019.06.043. [Epub ahead of print]

RAD51AP1 Is an Essential Mediator of Alternative Lengthening of Telomeres.

Author information

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
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.
5
Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA. Electronic address: osullivanr@upmc.edu.

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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