RAD51AP1 is an essential mediator of Alternative Lengthening of Telomeres

Published: 18 July 2019| Version 3 | DOI: 10.17632/7frzkkgz74.3
Contributors:
jonathan barroso-gonzalez,
roderick o'sullivan

Description

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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