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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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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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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 (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.
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Microhomology-mediated end joining acts directly on replication forks to repair single-ended double-strand breaks.

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

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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, Yuqin Zhao1

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

Cell Reports
|October 2, 2025
PubMed
Summary

Defective senataxin (SETX) triggers break-induced replication (BIR) at DNA breaks with RNA/DNA hybrids. This uncovers a new role for BIR in repairing complex DNA damage and offers cancer treatment strategies.

Keywords:
CP: Molecular biologyMRE11PIF1R-loopRAD52XPFbreak-induced replicationdouble-strand breakend resectionhomologous recombinationsenataxin

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Area of Science:

  • DNA repair mechanisms
  • Molecular biology
  • Genetics

Background:

  • Break-induced replication (BIR) primarily repairs single-ended double-strand breaks (seDSBs) at replication forks and telomeres.
  • Senataxin (SETX) is an RNA/DNA helicase involved in resolving DNA structures.

Purpose of the Study:

  • To investigate the role of SETX in DNA double-strand break (DSB) repair.
  • To explore the mechanism of BIR at R-loop/hybrid-accumulated double-ended DSBs (deDSBs) in the absence of SETX.

Main Methods:

  • Investigated DNA repair pathways in senataxin-deficient cells.
  • Analyzed the role of RAD52, XPF, and PIF1 in BIR.
  • Studied the impact of RNA/DNA hybrids on DNA synthesis and repair.

Main Results:

  • Loss of SETX induces hyper-recombination via BIR at R-loop/hybrid-accumulated deDSBs.
  • SETX deficiency triggers non-canonical hyper-end resection and stalls DNA synthesis due to RNA/DNA hybrids.
  • PCNA ubiquitination and PIF1 loading initiate BIR at deDSBs, further enhanced by hyper-resection.

Conclusions:

  • Uncovered a novel role for BIR in repairing R-loop/hybrid-associated deDSBs.
  • Dysfunctional SETX exhibits synthetic lethality with loss of PIF1, RAD52, or XPF.
  • Identified potential therapeutic strategies for SETX-deficient tumors targeting these pathways.