Extrachromosomal telomere repeat DNA is linked to ALT development via cGAS-STING DNA sensing pathway.
Nat Struct Mol Biol
; 24(12): 1124-1131, 2017 Dec.
Article
in En
| MEDLINE
| ID: mdl-29106411
ABSTRACT
Extrachromosomal telomere repeat (ECTR) DNA is unique to cancer cells that maintain telomeres through the alternative lengthening of telomeres (ALT) pathway, but the role of ECTRs in ALT development remains elusive. We found that induction of ECTRs in normal human fibroblasts activated the cGAS-STING-TBK1-IRF3 signaling axis to trigger IFNß production and a type I interferon response, resulting in cell-proliferation defects. In contrast, ALT cancer cells are commonly defective in sensing cytosolic DNA. We found that STING expression was inhibited in ALT cancer cell lines and transformed ALT cells. Notably, the ALT suppressors histone H3.3 and the ATRX-Daxx histone chaperone complex were also required to activate the DNA-sensing pathway. Collectively, our data suggest that the loss of the cGAS-STING pathway may be required to evade ECTR-induced anti-proliferation effects and permit ALT development, and this requirement may be exploited for treatments specific to cancers utilizing the ALT pathway.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Telomere
/
Interferon-beta
/
Protein Serine-Threonine Kinases
/
Cell Proliferation
/
Interferon Regulatory Factor-3
/
Membrane Proteins
/
Nucleotidyltransferases
Limits:
Humans
Language:
En
Journal:
Nat Struct Mol Biol
Journal subject:
BIOLOGIA MOLECULAR
Year:
2017
Document type:
Article
Affiliation country:
Taiwán