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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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Topoisomerases are enzymes that relax overwound DNA molecules during various cell processes, including DNA replication and transcription. These enzymes regulate positive and negative DNA supercoiling without changing the nucleotide sequence. DNA overwinding in a clockwise direction results in positively supercoiled DNA, whereas underwinding in a counterclockwise direction produces negatively supercoiled DNA.
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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: Aug 27, 2025

Author Spotlight: Unveiling the Role of SNF2L in Replication Fork Stability and Genome Duplication
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Topoisomerase 1-dependent R-loop deficiency drives accelerated replication and genomic instability.

Dan Sarni1, Sonia Barroso2, Alon Shtrikman1

  • 1Department of Genetics, The Life Sciences Institute, The Hebrew University, Jerusalem 91904, Israel.

Cell Reports
|September 28, 2022
PubMed
Summary

Accelerated DNA replication, a new form of replication stress, is caused by increased topoisomerase 1 (TOP1) expression. This leads to DNA damage by altering RNA-DNA hybrids (R-loops), impacting genome integrity.

Keywords:
CP: Molecular biologyDNA replicationR loopsgenomic instabilityoncogenesreplication stresstopoisomerase 1

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Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • DNA replication ensures genome duplication, but stress can cause damage and instability.
  • Replication stress often involves slow or stalled forks, but accelerated replication is a newly recognized form.
  • The molecular mechanisms driving accelerated replication remain largely unknown.

Purpose of the Study:

  • To investigate the molecular basis of oncogene-induced accelerated DNA replication.
  • To elucidate the role of topoisomerase 1 (TOP1) in replication fork dynamics and DNA damage.
  • To understand how R-loop homeostasis is maintained during DNA replication.

Main Methods:

  • Analysis of cells with mutated HRAS activation.
  • Measurement of topoisomerase 1 (TOP1) expression levels.
  • Assessment of replication fork speed and DNA damage markers.
  • Investigating the impact of TOP1 and RNaseH1 modulation on replication and R-loops.

Main Results:

  • Mutated HRAS activation increases TOP1 expression, leading to aberrant replication fork acceleration.
  • Increased TOP1 reduces RNA-DNA hybrids (R-loops), causing DNA damage.
  • Restoring TOP1 levels or mild replication inhibition rescues replication and reduces DNA damage.
  • Overexpression of TOP1 or RNaseH1 induces accelerated replication and DNA damage.

Conclusions:

  • Aberrant replication fork acceleration is a mechanism of oncogene-induced DNA damage.
  • TOP1 plays a critical role in maintaining R-loop homeostasis for genome integrity.
  • TOP1 equilibrium is essential for faithful DNA replication and preventing genomic instability.