RAD51AP1 Is an Essential Mediator of Alternative Lengthening of Telomeres.
Autophagy
Autophagy-Related Protein 7
/ genetics
Autophagy-Related Protein-1 Homolog
/ genetics
Cell Proliferation
DNA Polymerase III
/ genetics
DNA-Binding Proteins
/ genetics
Gene Expression Regulation, Neoplastic
HEK293 Cells
HeLa Cells
Homologous Recombination
Humans
Intracellular Signaling Peptides and Proteins
/ genetics
Ligases
/ genetics
Lysine
Neoplasms
/ genetics
Nucleotidyltransferases
/ genetics
Protein Stability
RNA-Binding Proteins
/ genetics
Rad52 DNA Repair and Recombination Protein
/ genetics
Signal Transduction
Sumoylation
Telomere
/ genetics
Telomere Homeostasis
RAD51AP1
SUMOylation
autophagy
cancer
homology-directed repair
telomere
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
03 10 2019
03 10 2019
Historique:
received:
15
11
2018
revised:
23
05
2019
accepted:
26
06
2019
pubmed:
12
8
2019
medline:
20
2
2020
entrez:
12
8
2019
Statut:
ppublish
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.
Identifiants
pubmed: 31400850
pii: S1097-2765(19)30500-3
doi: 10.1016/j.molcel.2019.06.043
pmc: PMC6778027
mid: NIHMS1533834
pii:
doi:
Substances chimiques
DNA-Binding Proteins
0
Intracellular Signaling Peptides and Proteins
0
RAD51AP1 protein, human
0
RAD52 protein, human
0
RNA-Binding Proteins
0
Rad52 DNA Repair and Recombination Protein
0
Autophagy-Related Protein-1 Homolog
EC 2.7.11.1
ULK1 protein, human
EC 2.7.11.1
Nucleotidyltransferases
EC 2.7.7.-
POLD3 protein, human
EC 2.7.7.-
cGAS protein, human
EC 2.7.7.-
DNA Polymerase III
EC 2.7.7.7
Ligases
EC 6.-
ATG7 protein, human
EC 6.2.1.45
Autophagy-Related Protein 7
EC 6.2.1.45
NSMCE2 protein, human
EC 6.3.2.-
Lysine
K3Z4F929H6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Video-Audio Media
Langues
eng
Sous-ensembles de citation
IM
Pagination
11-26.e7Subventions
Organisme : NIH HHS
ID : S10 OD019973
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES024872
Pays : United States
Organisme : NIH HHS
ID : S10 OD010625
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA047904
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA207209
Pays : United States
Commentaires et corrections
Type : ErratumIn
Type : ErratumIn
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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