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Using Next Generation Sequencing to Identify Mutations Associated with Repair of a CAS9-induced Double Strand Break Near the CD4 Promoter
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Using Next Generation Sequencing to Identify Mutations Associated with Repair of a CAS9-induced Double Strand Break Near the CD4 Promoter

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CsA can induce DNA double-strand breaks: implications for BMT regimens particularly for individuals with defective

M O'Driscoll1, P A Jeggo

  • 1Genome Damage and Stability Centre, University of Sussex, Brighton, East Sussex, UK.

Bone Marrow Transplantation
|February 19, 2008
PubMed

Insights

DNA ligase IV syndrome (LIG4) patients show unexpected sensitivity to CsA, a common GVHD prophylaxis. This drug induces DNA double-strand breaks (DSBs) that LIG4 cells cannot repair, impacting BMT and GVHD management.

Area of Science:

  • Molecular Biology
  • Genetics
  • Immunology

Background:

  • Mutations in non-homologous end joining (NHEJ) pathway components cause human disorders with DSB sensitivity.
  • DNA ligase IV syndrome (LIG4) patients exhibit poor outcomes post-bone marrow transplant (BMT) and malignancy treatment.
  • The specific reasons for LIG4 syndrome patient sensitivity to BMT conditioning are unknown.

Purpose of the Study:

  • To evaluate the response of LIG4 syndrome to standard BMT conditioning agents.
  • To investigate the effect of Cyclosporine A (CsA) on LIG4 syndrome cells.

Main Methods:

  • Systematic evaluation of LIG4 syndrome response to BMT conditioning compounds.
  • Assessment of human pre-B lymphocytes deficient for DNA ligase IV.
  • Analysis of DNA double-strand breaks (DSBs) after treatment with CsA, busulfan (BU), and fludarabine.

Main Results:

  • LIG4 syndrome pre-B lymphocytes are unexpectedly sensitive to CsA, a primary prophylaxis for graft-versus-host disease (GVHD).
  • CsA, alone or with BU and fludarabine, increased DSBs in LIG4 syndrome cells compared to wild-type or Artemis-deficient cells.
  • CsA induces DSBs, which LIG4 syndrome cells fail to repair, likely due to DNA replication issues.

Conclusions:

  • Cyclosporine A (CsA) can induce DNA double-strand breaks (DSBs).
  • LIG4 syndrome patients are unable to adequately repair CsA-induced DSBs.
  • Findings have implications for managing BMT and GVHD, particularly in LIG4 syndrome patients.

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