The mechanism of checkpoint-dependent DNA replication fork stabilization in human cells DOI Creative Commons
Agustina P. Bertolin, Berta Canal,

Mona Yekezare

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 3, 2024

Summary The DNA damage checkpoint is crucial for maintaining genome stability after genotoxic stress; without it, excess replication origins are activated, stalled forks cannot restart normally, high levels of and single-stranded (ssDNA) accumulate cells complete S phase. Preventing origin firing suppresses all these effects. Here we show that when not restrained by a functional checkpoint, synthesis sequesters the processivity factor PCNA its loader RFC, preventing normal fork restart. Nascent ends unprotected RFC/PCNA attacked Helicase-Like Transcription Factor (HLTF), causing irreversible collapse hyperaccumulation DNA. This explains how stabilizes has implications normally coordinated with progression. Loss HLTF cell lethality in checkpoint-deficient cells, which resistance to anti-checkpoint therapies may arise.

Language: Английский

Profound synthetic lethality between SMARCAL1 and FANCM DOI

Sumin Feng,

Kaiwen Liu,

Jinfeng Shang

et al.

Molecular Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Language: Английский

Citations

2
Strand dependent bypass of DNA lesions during fork reversal by ATP-dependent translocases SMARCAL1, ZRANB3, and HLTF DOI Creative Commons
Madison B. Adolph, Garrett M. Warren,

Frank B. Couch

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 19, 2024

Abstract During DNA replication, the replisome encounters obstacles including lesions, transcription-replication conflicts, and other sources of replication stress. These must be efficiently overcome to complete synthesis minimize genome instability. One pathway tolerate stress is fork reversal, in which parental template strands are reannealed a nascent-nascent duplex formed. Several enzymes promote ATP-dependent translocases SMARCAL1, ZRANB3, HLTF. How these translocate on that contains fork-stalling lesions unknown. Here, we examined abilities HLTF various leading or lagging strands. We demonstrate SMARCAL1 ZRANB3 selectively inhibited by strand, whereas insensitive bulky either strand. results suggest contact strand during reversal therefore more sensitive inhibition this In contrast, translocation inherently lesions. biochemical differences between provide insights into their mechanism remodeling they may act lesion-specific contexts.

Language: Английский

Citations

0
The mechanism of checkpoint-dependent DNA replication fork stabilization in human cells DOI Creative Commons
Agustina P. Bertolin, Berta Canal,

Mona Yekezare

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 3, 2024

Summary The DNA damage checkpoint is crucial for maintaining genome stability after genotoxic stress; without it, excess replication origins are activated, stalled forks cannot restart normally, high levels of and single-stranded (ssDNA) accumulate cells complete S phase. Preventing origin firing suppresses all these effects. Here we show that when not restrained by a functional checkpoint, synthesis sequesters the processivity factor PCNA its loader RFC, preventing normal fork restart. Nascent ends unprotected RFC/PCNA attacked Helicase-Like Transcription Factor (HLTF), causing irreversible collapse hyperaccumulation DNA. This explains how stabilizes has implications normally coordinated with progression. Loss HLTF cell lethality in checkpoint-deficient cells, which resistance to anti-checkpoint therapies may arise.

Language: Английский

Citations

0