CST-polymerase α-primase solves a second telomere end-replication problem.
Nature
; 627(8004): 664-670, 2024 Mar.
Article
in En
| MEDLINE
| ID: mdl-38418884
ABSTRACT
Telomerase adds G-rich telomeric repeats to the 3' ends of telomeres1, counteracting telomere shortening caused by loss of telomeric 3' overhangs during leading-strand DNA synthesis ('the end-replication problem'2). Here we report a second end-replication problem that originates from the incomplete duplication of the C-rich telomeric repeat strand (C-strand) by lagging-strand DNA synthesis. This problem is resolved by fill-in synthesis mediated by polymerase α-primase bound to Ctc1-Stn1-Ten1 (CST-Polα-primase). In vitro, priming for lagging-strand DNA replication does not occur on the 3' overhang and lagging-strand synthesis stops in a zone of approximately 150 nucleotides (nt) more than 26 nt from the end of the template. Consistent with the in vitro data, lagging-end telomeres of cells lacking CST-Polα-primase lost 50-60 nt of telomeric CCCTAA repeats per population doubling. The C-strands of leading-end telomeres shortened by around 100 nt per population doubling, reflecting the generation of 3' overhangs through resection. The measured overall C-strand shortening in the absence of CST-Polα-primase fill-in is consistent with the combined effects of incomplete lagging-strand synthesis and 5' resection at the leading ends. We conclude that canonical DNA replication creates two telomere end-replication problems that require telomerase to maintain the G-rich strand and CST-Polα-primase to maintain the C-strand.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Telomere
/
DNA Primase
/
Telomere-Binding Proteins
/
DNA Polymerase I
/
DNA Replication
Limits:
Humans
Language:
En
Journal:
Nature
/
Nature (Lond.)
/
Nature (London)
Year:
2024
Document type:
Article
Affiliation country:
Estados Unidos
Country of publication:
Reino Unido