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Modeling oncogenic translocations: distinct roles for double-strand break repair pathways in translocation formation

David M Weinstock1, Christine A Richardson, Beth Elliott

  • 1Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.

DNA Repair
|July 4, 2006
PubMed

Insights

DNA double-strand breaks (DSBs) can cause tumors. This review highlights how non-homologous end-joining (NHEJ) efficiently creates translocations, while homologous recombination (HR) and single-strand annealing (SSA) are less effective.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Research

Background:

  • Reciprocal chromosomal translocations are key drivers in various cancers, including leukemias, lymphomas, and sarcomas.
  • DNA double-strand breaks (DSBs) are the primary precursors to these translocations, arising from cellular processes or external factors.
  • Mammalian cells employ multiple DNA repair pathways, including non-homologous end-joining (NHEJ), homologous recombination (HR), and single-strand annealing (SSA), to resolve DSBs.

Purpose of the Study:

  • To review reporter systems used to assess the capacity of different DSB repair pathways in mediating translocation formation in mammalian cells.
  • To elucidate the specific roles and efficiencies of NHEJ, HR, and SSA in generating chromosomal translocations.

Main Methods:

  • Utilizing various reporter systems designed to detect translocation events mediated by specific DNA repair pathways.
  • Analyzing data from studies employing these reporters to quantify the translocation frequencies associated with NHEJ, HR, and SSA.
  • Comparing the mechanistic underpinnings of each repair pathway's involvement in translocation formation.

Main Results:

  • Non-homologous end-joining (NHEJ) is highly efficient in mediating the formation of chromosomal translocations.
  • Homologous recombination (HR) demonstrates limited translocation formation capacity due to inherent crossover suppression mechanisms.
  • Single-strand annealing (SSA) can efficiently mediate translocations between identical repeats but contributes minimally to overall translocation formation due to sequence divergence in the genome.

Conclusions:

  • NHEJ is the predominant pathway responsible for generating translocations implicated in tumorigenesis.
  • HR and SSA play significantly lesser roles in translocation formation compared to NHEJ.
  • Understanding these repair pathway dynamics is crucial for comprehending the etiology of translocation-associated cancers.

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