DNA sequence selectivity of human topoisomerase I-mediated DNA cleavage induced by camptothecin

Chandanamali Punchihewa, Megan Carver, Danzhou Yang

Research output: Contribution to journalArticle

Abstract

In probing the mechanism of inhibition of hypoxia inducible factor (HIF-1) by campothecins, we investigated the ability of human topoisomerase I to bind and cleave HIF-1 response element (HRE), which contains the known camptothecin-mediated topoisomerase I cleavage site 5′-TG. We observed that the selection of 5′-TG by human topoisomerase I and topotecan depends to a large extent on the specific flanking sequences, and that the presence of a G at the -2 position (where cleavage occurs between -1 and +1) prevents the HRE site from being a preferred site for such cleavage. Furthermore, the presence of -2 T/A can induce the cleavage at a less preferred TC or TA site. However, in the absence of a more preferred site, the HRE site is shown to be cleaved by human topoisomerase I in the presence of topotecan. Thus, it is implied that the -2 base has a significant influence on the selection of the camptothecinmediated Topo I cleavage site, which can overcome the preference for +1G. While the cleavage site recognition has been known to be based on the concerted effect of several bases spanning the cleavage site, such a determining effect of an individual base has not been previously recognized. A possible base-specific interaction between DNA and topoisomerase I may be responsible for this sequence selectivity.

Original languageEnglish (US)
Pages (from-to)1326-1331
Number of pages6
JournalProtein Science
Volume18
Issue number6
DOIs
StatePublished - Jun 1 2009

Keywords

  • Camptothecin
  • DNA cleavage site
  • HIF-1 response element
  • Human topoisomerase I

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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