PrimPol-mediated repriming facilitates replication traverse of DNA interstrand crosslinks.
EMBO J
; 40(14): e106355, 2021 07 15.
Article
in En
| MEDLINE
| ID: mdl-34128550
ABSTRACT
DNA interstrand crosslinks (ICLs) induced by endogenous aldehydes or chemotherapeutic agents interfere with essential processes such as replication and transcription. ICL recognition and repair by the Fanconi Anemia pathway require the formation of an X-shaped DNA structure that may arise from convergence of two replication forks at the crosslink or traversing of the lesion by a single replication fork. Here, we report that ICL traverse strictly requires DNA repriming events downstream of the lesion, which are carried out by PrimPol, the second primase-polymerase identified in mammalian cells after Polα/Primase. The recruitment of PrimPol to the vicinity of ICLs depends on its interaction with RPA, but not on FANCM translocase or the BLM/TOP3A/RMI1-2 (BTR) complex that also participate in ICL traverse. Genetic ablation of PRIMPOL makes cells more dependent on the fork convergence mechanism to initiate ICL repair, and PRIMPOL KO cells and mice display hypersensitivity to ICL-inducing drugs. These results open the possibility of targeting PrimPol activity to enhance the efficacy of chemotherapy based on DNA crosslinking agents.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
DNA
/
DNA Primase
/
DNA-Directed DNA Polymerase
/
DNA Replication
/
Multifunctional Enzymes
Limits:
Animals
/
Female
/
Humans
/
Male
Language:
En
Journal:
EMBO J
Year:
2021
Type:
Article
Affiliation country:
Spain