En direct

Mieux comprendre le vieillissement des cellules souches hématopoïétiques par une approche transcriptomique à l’échelle de la cellule unique -

10 2019 Molecular cell

RAD51AP1 Is an Essential Mediator of Alternative Lengthening of Telomeres.

Auteurs

Barroso-González J, García-Expósito L, Hoang SM, Lynskey ML, Roncaioli JL, Ghosh A, Wallace CT, Modesti M, Bernstein KA, Sarkar SN, Watkins SC, O'Sullivan RJ

Résumé

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.

Lire l‘article