Molecular cell, 2019-10, Vol.76 (1), p.11-26.e7
2019
Details
- Autor(en) / Beteiligte
- Titel
- RAD51AP1 Is an Essential Mediator of Alternative Lengthening of Telomeres
- Ist Teil von
- Molecular cell, 2019-10, Vol.76 (1), p.11-26.e7
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2019
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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. [Display omitted] •Disruption of RAD51AP1 inhibits telomere homology-directed repair in ALT cancer cells•cGAS-ULK1-ATG7-dependent autophagy is activated upon telomere dysfunction•RAD51AP1 is specifically stabilized and regulated by SUMOylation Barroso-González et al. identify that disruption of the HR accessory factor RAD51AP1 disrupts ALT telomere elongation, causing telomere damage and fragmentation. Rather than dying, these cancer cells activate autophagy as a survival mechanism. The importance of RAD51AP1 in ALT cancer cells is underscored by its specific stabilization by SUMOylated mediated mechanisms.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1097-2765eISSN: 1097-4164DOI: 10.1016/j.molcel.2019.06.043Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6778027
- Format
- –
- Schlagworte
- Autophagy, Autophagy-Related Protein 7 - genetics, Autophagy-Related Protein 7 - metabolism, Autophagy-Related Protein-1 Homolog - genetics, Autophagy-Related Protein-1 Homolog - metabolism, cancer, 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, homology-directed repair, Humans, Intracellular Signaling Peptides and Proteins - genetics, Intracellular Signaling Peptides and Proteins - metabolism, Life Sciences, Ligases - genetics, Ligases - metabolism, Lysine, Neoplasms - genetics, Neoplasms - metabolism, Neoplasms - pathology, Nucleotidyltransferases - genetics, Nucleotidyltransferases - metabolism, Protein Stability, RAD51AP1, Rad52 DNA Repair and Recombination Protein - genetics, Rad52 DNA Repair and Recombination Protein - metabolism, RNA-Binding Proteins - genetics, RNA-Binding Proteins - metabolism, Signal Transduction, SUMOylation, telomere, Telomere - genetics, Telomere - metabolism, Telomere - pathology, Telomere Homeostasis