TRF2-mediated ORC recruitment underlies telomere stability upon DNA replication stress.
Nucleic Acids Res
; 49(21): 12234-12251, 2021 12 02.
Article
de En
| MEDLINE
| ID: mdl-34761263
ABSTRACT
Telomeres are intrinsically difficult-to-replicate region of eukaryotic chromosomes. Telomeric repeat binding factor 2 (TRF2) binds to origin recognition complex (ORC) to facilitate the loading of ORC and the replicative helicase MCM complex onto DNA at telomeres. However, the biological significance of the TRF2-ORC interaction for telomere maintenance remains largely elusive. Here, we employed a TRF2 mutant with mutations in two acidic acid residues (E111A and E112A) that inhibited the TRF2-ORC interaction in human cells. The TRF2 mutant was impaired in ORC recruitment to telomeres and showed increased replication stress-associated telomeric DNA damage and telomere instability. Furthermore, overexpression of an ORC1 fragment (amino acids 244-511), which competitively inhibited the TRF2-ORC interaction, increased telomeric DNA damage under replication stress conditions. Taken together, these findings suggest that TRF2-mediated ORC recruitment contributes to the suppression of telomere instability.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Télomère
/
Protéine-2 de liaison aux répétitions télomériques
/
Réplication de l'ADN
/
Complexe ORC
/
Mutation
Limites:
Humans
Langue:
En
Journal:
Nucleic Acids Res
Année:
2021
Type de document:
Article
Pays d'affiliation:
Japon