o%27driscoll_2008.pdf (1.25 MB)
CsA can induce DNA double-strand breaks: implications for BMT regimens particularly for individuals with defective DNA repair
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posted on 2023-06-15, 13:59 authored by Mark O'DriscollMark O'Driscoll, Penny JeggoSeveral human disorders mutated in core components of the major DNA double-strand break (DSB) repair pathway, non-homologous end joining (NHEJ), have been described. Cell lines from these patients are characterized by sensitivity to DSB-inducing agents. DNA ligase IV syndrome (LIG4) patients specifically, for unknown reasons, respond particularly badly following treatment for malignancy or BMT. We report the first systematic evaluation of the response of LIG4 syndrome to compounds routinely employed for BMT conditioning. We found human pre-B lymphocytes, a key target population for BMT conditioning, when deficient for DNA ligase IV, unexpectedly exhibit significant sensitivity to CsA the principal prophylaxis for GVHD. Furthermore, we found that CsA treatment alone or in combination with BU and fludarabine resulted in increased levels of DSBs specifically in LIG4 syndrome cells compared to wild-type or Artemis-deficient cells. Our study shows that CsA can induce DSBs and that LIG4 syndrome patient's fail to adequately repair this damage. These DSBs likely arise as a consequence of DNA replication in the presence of CsA. This work has implications for BMT and GVHD management in general and specifically for LIG4 syndrome.
History
Publication status
- Published
File Version
- Accepted version
Journal
Bone Marrow TransplantationISSN
0268-3369Publisher
Nature Publishing GroupExternal DOI
Issue
11Volume
41Page range
983-989Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2012-02-06First Open Access (FOA) Date
2018-05-11First Compliant Deposit (FCD) Date
2018-05-11Usage metrics
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