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Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
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Updated: Mar 29, 2026

CIRCLE-Seq for Interrogation of Off-Target Gene Editing
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RAG Off-Target Activity Is in the Loop.

Lili Blumenberg1, Jane A Skok1

  • 1Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.

Trends in Molecular Medicine
|November 26, 2015
PubMed
Summary
This summary is machine-generated.

RAG recombinase off-target activity, a cause of mutations and cancer, is limited by DNA regulatory elements. These joining events are restricted to specific DNA elements within chromatin loop domains.

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Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Recombination-activating gene (RAG) recombinases mediate V(D)J recombination but can cause off-target activity, contributing to mutations and cancer.
  • DNA regulatory elements influence gene activity, with their effects often constrained by chromatin looping and interaction frequencies.

Purpose of the Study:

  • To investigate the limitations on RAG off-target activity.
  • To determine if RAG off-target activity is influenced by chromatin structure.

Main Methods:

  • Analysis of RAG off-target activity in relation to DNA regulatory elements.
  • Examination of chromatin loop formation and interaction frequencies.

Main Results:

  • Major RAG off-target activity was identified.
  • This off-target activity was found to be limited by similar constraints as DNA regulatory elements.
  • Joining events were restricted to convergent paired RSS (recombination signal sequences) elements within loop domains.

Conclusions:

  • RAG off-target activity is spatially constrained by chromatin architecture.
  • Understanding these limitations may offer new strategies for cancer prevention and treatment.