RAD51AP1 Promotes Maintenance of Telomere Length in ALT+ Cancer Cells

Cancer cells require a mechanism to maintain telomere length. Although most cancers achieve this by reactivating telomerase, there also exists a separate mechanism called alternative lengthening of telomeres (ALT) that involves RAD51-dependent homologous recombination (HR) followed by break-induced telomere DNA synthesis (BITS). In multiple ALT⁺ cancer cell lines, Barroso-González and colleagues found that the vertebrate-specific RAD51 partner RAD51AP1 localized to telomeres, and depletion of RAD51AP1 led to telomere fragility and shortening similar to that seen in cells lacking a telomere-elongation mechanism. RAD51AP1 mediated both HR and BITS at telomeres in ALT⁺ cells, and lack of RAD51AP1 disrupted recruitment of the homology-dependent repair (HDR) factors POLD3 and RAD52 to telomeres. Telomeric DNA fragments expelled into the cytosol in RAD51AP1-deficient ALT⁺ cells were sensed by cyclic GMP–AMP synthase, triggering AMPK–ULK1-dependent autophagy and promoting cellular survival. MMS21-dependent SUMOylation of RAD51AP1 stabilized RAD51AP1, which led to increased levels of RAD51AP1 in ALT⁺ cancer cells. Further, SUMOylation of RAD51AP1 was critical for ALT and maintenance of telomere length. Collectively, these results demonstrate a previously unknown role for RAD51AP1 in ALT and suggest that investigation of combined inhibition of HDR and autophagy in ALT⁺ cancers may be warranted.

Barroso-González J, García-Expósito L, Hoang SM, Lynskey ML, Roncaioli JL, Ghosh A, et al. RAD51AP1 is an essential mediator of alternative lengthening of telomeres. Mol Cell 2019 Aug 7 [Epub ahead of print].

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.