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RAD51AP1 Is an Essential Mediator of Alternative Lengthening of Telomeres.

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.

journal_name

Mol Cell

journal_title

Molecular cell

authors

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

doi

10.1016/j.molcel.2019.06.043

subject

Has Abstract

pub_date

2019-10-03 00:00:00

pages

11-26.e7

issue

1

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(19)30500-3

journal_volume

76

pub_type

杂志文章

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