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Homologous Recombination02:31

Homologous Recombination

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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...
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Restarting Stalled Replication Forks02:37

Restarting Stalled Replication Forks

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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,...
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Fixing Double-strand Breaks02:04

Fixing Double-strand Breaks

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The double-stranded structure of DNA has two major advantages. First, it serves as a safe repository of genetic information where one strand serves as the back-up in case the other strand is damaged. Second, the double-helical structure can be wrapped around proteins called histones to form nucleosomes, which can then be tightly wound to form chromosomes. This way, DNA chains up to 2 inches long can be contained within microscopic structures in a cell. A double-stranded break not only damages...
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Translesion DNA Polymerases02:10

Translesion DNA Polymerases

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Translesion (TLS) polymerases rescue stalled DNA polymerases at sites of damaged bases by replacing the replicative polymerase and installing a nucleotide across the damaged site. Doing so, TLS allows additional time for the cell to repair the damage before resuming regular DNA replication.
TLS polymerases are found in all three domains of life - archaea, bacteria, and eukaryotes. Of the different classes of TLS polymerases, members of the Y family are fitted with specialized structures that...
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DNA Damage can Stall the Cell Cycle02:37

DNA Damage can Stall the Cell Cycle

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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...
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The DNA Replication Fork01:02

The DNA Replication Fork

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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...
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Updated: Sep 19, 2025

Visualization of DNA Repair Proteins Interaction by Immunofluorescence
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Visualization of DNA Repair Proteins Interaction by Immunofluorescence

Published on: June 26, 2020

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Break-induced replication is activated to repair R-loop-associated double-strand breaks in SETX-deficient cells.

Tong Wu1, Youhang Li1, Linda Z Shi2

  • 1Department of Molecular and Cell Biology, The Scripps Research Institute, La Jolla, CA 92037.

Biorxiv : the Preprint Server for Biology
|June 6, 2025
PubMed
Summary

Defective senataxin (SETX) triggers break-induced replication (BIR) at double-ended double-strand breaks (deDSBs) by stalling DNA synthesis due to RNA/DNA hybrids. This uncovers a novel role for BIR in repairing deDSBs and suggests new cancer treatment strategies.

Keywords:
Break-induced replication (BIR)MRE11PIF1R-loopRAD52Senataxin (SETX)XPFdouble-strand break (DSB)end resectionhomologous recombination (HR)

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Detection of Homologous Recombination Intermediates via Proximity Ligation and Quantitative PCR in Saccharomyces cerevisiae
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Application of Laser Micro-irradiation for Examination of Single and Double Strand Break Repair in Mammalian Cells
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Application of Laser Micro-irradiation for Examination of Single and Double Strand Break Repair in Mammalian Cells

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Area of Science:

  • Molecular Biology
  • DNA Repair Mechanisms
  • Genetics

Background:

  • Break-induced replication (BIR) primarily repairs single-ended double-strand breaks (seDSBs) at broken replication forks and telomeres.
  • Senataxin (SETX), an RNA/DNA helicase, plays a role in resolving DNA structures.
  • Double-ended double-strand breaks (deDSBs) present unique repair challenges.

Purpose of the Study:

  • To investigate the role of SETX in DNA repair, particularly concerning double-ended double-strand breaks (deDSBs).
  • To elucidate the mechanism by which SETX deficiency impacts DNA repair pathways.
  • To explore potential therapeutic strategies targeting SETX-deficient cells.

Main Methods:

  • Investigated DNA repair mechanisms in senataxin (SETX)-defective cells.
  • Analyzed the role of RAD52, XPF, and PIF1 in break-induced replication (BIR).
  • Studied the impact of RNA/DNA hybrids on DNA synthesis and repair.

Main Results:

  • Loss of SETX induces hyper-recombination via BIR at double-ended DSBs (deDSBs) that accumulate RNA/DNA hybrids.
  • SETX deficiency leads to non-canonical hyper-end resection and stalls DNA synthesis initiation at deDSBs.
  • Accumulation of RNA/DNA hybrids, PCNA ubiquitination, and PIF1 loading initiate BIR at deDSBs.
  • SETX exhibits synthetic lethality with PIF1, RAD52, and XPF.

Conclusions:

  • Uncovered a novel role for BIR in repairing R-loop/hybrid-associated deDSBs when SETX is defective.
  • Identified a conflict between DNA synthesis and hybrid structures that triggers BIR.
  • Demonstrated synthetic lethality between SETX and key DNA repair proteins, offering potential therapeutic avenues for SETX-deficient tumors.