Transcription-replication conflicts underlie sensitivity to PARP inhibitors.
Nature
; 628(8007): 433-441, 2024 Apr.
Article
in En
| MEDLINE
| ID: mdl-38509368
ABSTRACT
An important advance in cancer therapy has been the development of poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of homologous recombination (HR)-deficient cancers1-6. PARP inhibitors trap PARPs on DNA. The trapped PARPs are thought to block replisome progression, leading to formation of DNA double-strand breaks that require HR for repair7. Here we show that PARP1 functions together with TIMELESS and TIPIN to protect the replisome in early S phase from transcription-replication conflicts. Furthermore, the synthetic lethality of PARP inhibitors with HR deficiency is due to an inability to repair DNA damage caused by transcription-replication conflicts, rather than by trapped PARPs. Along these lines, inhibiting transcription elongation in early S phase rendered HR-deficient cells resistant to PARP inhibitors and depleting PARP1 by small-interfering RNA was synthetic lethal with HR deficiency. Thus, inhibiting PARP1 enzymatic activity may suffice for treatment efficacy in HR-deficient settings.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Transcription, Genetic
/
Poly(ADP-ribose) Polymerases
/
DNA Replication
/
Poly(ADP-ribose) Polymerase Inhibitors
Limits:
Humans
Language:
En
Journal:
Nature
Year:
2024
Document type:
Article
Affiliation country: