Related Experiment Video

Updated: Jun 28, 2025

Author Spotlight: Unveiling the Role of SNF2L in Replication Fork Stability and Genome Duplication
05:55

Author Spotlight: Unveiling the Role of SNF2L in Replication Fork Stability and Genome Duplication

Published on: August 23, 2024

503

UFL1 triggers replication fork degradation by MRE11 in BRCA1/2-deficient cells

Tian Tian1,2, Junliang Chen3, Huacun Zhao4

  • 1Zhejiang Key Laboratory of Geriatrics and Geriatrics Institute of Zhejiang Province, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Nature Chemical Biology
|April 22, 2024
PubMed

Insights

UFL1 stabilizes stalled replication forks in BRCA1/2-deficient tumors, conferring resistance to PARP inhibitors. Its loss or disruption of PTIP UFMylation protects DNA and enhances treatment resistance.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • Replication fork stability is crucial for preventing genomic instability in cancer.
  • Resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient tumors is often mediated by mechanisms that stabilize stalled replication forks.
  • Understanding these resistance mechanisms is vital for developing effective cancer therapies.

Purpose of the Study:

  • To identify key regulators of replication fork stability in the context of PARP inhibitor resistance.
  • To elucidate the molecular mechanisms by which UFL1 influences fork stability and PARP inhibitor response.
  • To explore potential therapeutic targets for overcoming PARP inhibitor resistance in BRCA1/2-deficient cancers.

Main Methods:

  • Utilized cell-based assays to study replication fork dynamics under replication stress.
  • Employed biochemical techniques including immunoprecipitation and Western blotting to investigate protein interactions and modifications.
  • Analyzed the role of UFL1, UFMylation, and PTIP modification in regulating DNA strand integrity and PARP inhibitor sensitivity.

Main Results:

  • Identified UFL1, a UFM1-specific E3 ligase, as a critical regulator of fork stability in BRCA1/2-deficient cells.
  • Demonstrated that UFL1 catalyzes PTIP UFMylation at stalled forks, promoting MLL3/4 complex assembly and H3K4 methylation.
  • Showed that loss of UFL1, impaired PTIP UFMylation, or UFSP2 overexpression protects nascent DNA from degradation and confers resistance to PARP inhibitors.

Conclusions:

  • UFL1-mediated PTIP UFMylation is a novel mechanism that stabilizes stalled replication forks and drives PARP inhibitor resistance in BRCA1/2-deficient tumors.
  • Targeting the UFL1-PTIP axis could offer a strategy to sensitize BRCA1/2-deficient tumors to PARP inhibitors.
  • These findings provide critical mechanistic insights into therapeutic resistance and suggest new avenues for cancer treatment.

More Related Videos

Visualization of DNA Repair Proteins Interaction by Immunofluorescence07:55

Visualization of DNA Repair Proteins Interaction by Immunofluorescence

Published on: June 26, 2020

10.2K
Identifying the Effects of BRCA1 Mutations on Homologous Recombination using Cells that Express Endogenous Wild-type BRCA108:53

Identifying the Effects of BRCA1 Mutations on Homologous Recombination using Cells that Express Endogenous Wild-type BRCA1

Published on: February 17, 2011

14.7K

Related Concept Videos

Restarting Stalled Replication Forks02:37

Restarting Stalled Replication Forks

DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
5.8K
The DNA Replication Fork01:02

The DNA Replication Fork

An organism’s genome needs to be duplicated in an efficient and error-free manner for its growth and survival. The replication fork is a Y-shaped active region where two strands of DNA are separated and replicated continuously. The coupling of DNA unzipping and complementary strand synthesis is a characteristic feature of a replication fork.   Organisms with small circular DNA, such as E. coli, often have a single origin of replication; therefore, they have only two replication...
35.9K
Homologous Recombination02:31

Homologous Recombination

The basic reaction of homologous recombination (HR) involves two chromatids that contain DNA sequences sharing a significant stretch of identity. One of these sequences uses a strand from another as a template to synthesize DNA in an enzyme-catalyzed reaction. The final product is a novel amalgamation of the two substrates. To ensure an accurate recombination of sequences, HR is restricted to the S and G2 phases of the cell cycle. At these stages, the DNA has been replicated already and the...
50.5K
Long-patch Base Excision Repair01:02

Long-patch Base Excision Repair

Since the discovery of the two BER pathways, there has been a debate about how a cell chooses one pathway over the other and the factors determining this selection. Numerous in vitro experiments have pointed out multiple determinants for the sub-pathway selection. These are:
7.0K
Nucleotide Excision Repair01:08

Nucleotide Excision Repair

Overview
37.0K
DNA Damage can Stall the Cell Cycle02:37

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
9.1K