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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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DNA replication is carried out by a large complex of proteins that act in a coordinated matter to achieve high-fidelity DNA replication. Together this complex is known as the DNA replication machinery or the replisome.
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Related Experiment Video

Updated: Mar 15, 2026

Inducing a Site Specific Replication Blockage in E. coli Using a Fluorescent Repressor Operator System
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EEPD1 evolved a unique DNA clamping dimer protecting reversed replication forks.

Runze Shen1, Altaf H Sarker2, Yue Chen3

  • 1Department of Molecular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.

Nucleic Acids Research
|March 14, 2026
PubMed
Summary
This summary is machine-generated.

EEPD1 protein unexpectedly clamps, not cleaves, DNA at replication forks. This function protects genome stability during oxidative stress and impacts cancer patient survival.

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Area of Science:

  • Molecular Biology
  • Structural Biology
  • Genomics

Background:

  • Exonuclease/endonuclease/phosphatase (EEP)-fold hydrolases are typically monomeric phosphodiesterases.
  • EEPD1's role in DNA stress responses and its nuclease activities were previously unclear.

Purpose of the Study:

  • To define the structure, assembly, and function of EEPD1 at stalled DNA replication forks.
  • To elucidate EEPD1's mechanism in DNA replication fork protection.

Main Methods:

  • Hybrid structural methods (SAXS, crystal, cryo-EM)
  • Biochemistry
  • Evolutionary analysis
  • Cancer genomics
  • Molecular and cell biology

Main Results:

  • EEPD1 forms a dimer utilizing unique EEP and tandem Helix-hairpin-Helix domains to clamp double-stranded DNA at reversed replication forks.
  • Structural studies revealed an unusual tryptophan handshake dimer, a conserved di-Trp-Pro pocket, and a conformational switch.
  • EEPD1 lacks intrinsic nuclease activity due to evolutionary loss of catalytic residues; it prevents MRE11-mediated degradation of reversed forks.
  • Cancer bioinformatics indicated EEPD1 association correlates with patient survival, particularly in the context of oxidative damage.

Conclusions:

  • EEPD1 functions as a DNA clamp, not a nuclease, to protect reversed replication forks.
  • This clamping mechanism is crucial for metazoan oxidative stress responses and maintaining genome stability.
  • EEPD1's role in fork protection has implications for cancer outcomes and genome stability.