Mechanism of DNA replication fork breakage and PARP1 hyperactivation during replication catastrophe DOI Creative Commons
Pedro Ortega, Elodie Bournique,

Junyi Li

et al.

Science Advances, Journal Year: 2025, Volume and Issue: 11(16)

Published: April 16, 2025

Ataxia telangiectasia and Rad3-related (ATR) inhibition triggers a surge in origin firing, resulting increased levels of single-stranded DNA (ssDNA) that rapidly deplete all available RPA. This leaves ssDNA unprotected susceptible to breakage, phenomenon known as replication catastrophe. However, the mechanism by which breaks remains unclear. Here, we reveal APOBEC3B is key enzyme targeting at forks, initiating reaction cascade induces fork collapse poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation. Mechanistically, demonstrate uracils generated forks are removed UNG2, abasic sites subsequently cleaved APE1 endonuclease. Moreover, show APE1-mediated cleavage critical enzymatic step for PARP1 hyperactivation cells, regardless how on DNA. Last, APOBEC3B-induced trapping double-strand drive cell sensitivity ATR inhibition, creating context synthetic lethality when coupled with PARP inhibitors.

Language: Английский

Transcription stress causes an inflammatory response via release of IL-1α DOI
Thomas D. J. Walker,

Jessica P Morris,

Leonie Unterholzner

et al.

Nature Structural & Molecular Biology, Journal Year: 2025, Volume and Issue: unknown

Published: April 11, 2025

Language: Английский

Citations

0
Mechanism of DNA replication fork breakage and PARP1 hyperactivation during replication catastrophe DOI Creative Commons
Pedro Ortega, Elodie Bournique,

Junyi Li

et al.

Science Advances, Journal Year: 2025, Volume and Issue: 11(16)

Published: April 16, 2025

Ataxia telangiectasia and Rad3-related (ATR) inhibition triggers a surge in origin firing, resulting increased levels of single-stranded DNA (ssDNA) that rapidly deplete all available RPA. This leaves ssDNA unprotected susceptible to breakage, phenomenon known as replication catastrophe. However, the mechanism by which breaks remains unclear. Here, we reveal APOBEC3B is key enzyme targeting at forks, initiating reaction cascade induces fork collapse poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation. Mechanistically, demonstrate uracils generated forks are removed UNG2, abasic sites subsequently cleaved APE1 endonuclease. Moreover, show APE1-mediated cleavage critical enzymatic step for PARP1 hyperactivation cells, regardless how on DNA. Last, APOBEC3B-induced trapping double-strand drive cell sensitivity ATR inhibition, creating context synthetic lethality when coupled with PARP inhibitors.

Language: Английский

Citations

0