Induction of DNA ligase I by 1-β-D-arabinosylcytosine and aphidicolin in MiaPaCa human pancreatic cancer cells

Daekyu Sun, Rheanna Urrabaz, Christoph Buzello, Myhanh Nguyen

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Exposure of MiaPaCa cells to 1-β-D-arabinosylcytosine (ara-C) resulted in an increase in DNA ligase levels up to threefold compared to that in the untreated control cells, despite significant growth inhibition. Increased levels of DNA ligase I protein appear to correlate with the appearance of increased mRNA levels. The [3H]thymidine incorporation experiment and the biochemical assay of total polymerase activity revealed that an increase in DNA ligase I levels after treatment with ara-C was not accompanied by an increase of DNA synthesis or an increased presence of DNA polymerase activity inside cells. When cells resumed DNA synthesis after drug treatment, DNA ligase I levels began to drop, indicating that increased DNA ligase I is not required for DNA synthesis. An increase in DNA ligase I was also observed in cells treated with aphidicolin, another inhibitor of DNA synthesis that inhibits DNA polymerases without incorporating itself into DNA, indicating that an increase in DNA ligase I levels could be caused by the arrest of DNA replication by these agents. Interestingly, caffeine, which is a well-known inhibitor of DNA damage checkpoint kinases, abrogated the increase in DNA ligase I in MiaPaCa cells treated with ara-C and aphidicolin, suggesting that caffeine-sensitive kinases might be important mediators in the pathway leading to the increase in DNA ligase I levels in response to anticancer drugs, including ara-C and aphidicolin. We propose that ara-C and aphidicolin induce damage to the DNA strand by arresting DNA replication forks and subsequently increase DNA ligase I levels to facilitate repair of DNA damage.

Original languageEnglish (US)
Pages (from-to)90-96
Number of pages7
JournalExperimental Cell Research
Volume280
Issue number1
DOIs
StatePublished - Jan 1 2002
Externally publishedYes

Keywords

  • DNA ligase I
  • DNA repair
  • MiaPaCa cell
  • ara-C

ASJC Scopus subject areas

  • Cell Biology

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