RAD51AP1 Is an Essential Mediator of Alternative Lengthening of Telomeres

Mol Cell. 2019 Oct 3;76(1):11-26.e7. doi: 10.1016/j.molcel.2019.06.043. Epub 2019 Aug 7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Autophagy
  • Autophagy-Related Protein 7 / genetics
  • Autophagy-Related Protein 7 / metabolism
  • Autophagy-Related Protein-1 Homolog / genetics
  • Autophagy-Related Protein-1 Homolog / metabolism
  • Cell Proliferation
  • DNA Polymerase III / genetics
  • DNA Polymerase III / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • HeLa Cells
  • Homologous Recombination
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Ligases / genetics
  • Ligases / metabolism
  • Lysine
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Nucleotidyltransferases / genetics
  • Nucleotidyltransferases / metabolism
  • Protein Stability
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Rad52 DNA Repair and Recombination Protein / genetics
  • Rad52 DNA Repair and Recombination Protein / metabolism
  • Signal Transduction
  • Sumoylation
  • Telomere / genetics
  • Telomere / metabolism*
  • Telomere / pathology
  • Telomere Homeostasis*

Substances

  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • RAD51AP1 protein, human
  • RAD52 protein, human
  • RNA-Binding Proteins
  • Rad52 DNA Repair and Recombination Protein
  • Autophagy-Related Protein-1 Homolog
  • ULK1 protein, human
  • Nucleotidyltransferases
  • POLD3 protein, human
  • cGAS protein, human
  • DNA Polymerase III
  • Ligases
  • Atg7 protein, human
  • Autophagy-Related Protein 7
  • NSMCE2 protein, human
  • Lysine