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Leukotriene biosynthesis inhibitor MK886 impedes DNA polymerase activity

Amit Ketkar1, Maroof K Zafar, Leena Maddukuri

  • 1Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205-7199, USA.

Chemical Research in Toxicology
|January 12, 2013
PubMed

Insights

MK886 inhibits DNA polymerases, showing increased potency against human DNA polymerase iota (hpol ι), a key enzyme in error-prone DNA repair. This study elucidates MK886

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Drug Discovery

Background:

  • Specialized DNA polymerases are crucial for DNA repair and replication stress responses, acting as barriers against senescence and genomic instability.
  • Cancer cells exploit these pathways to resist chemotherapy and radiation, making DNA polymerases potential therapeutic targets.
  • Previous screens identified MK886 as a potent inhibitor of human DNA polymerase kappa (hpol κ), but its specificity and mechanism were unclear.

Purpose of the Study:

  • To investigate the specificity of the DNA polymerase inhibitor MK886 against various human Y-family DNA polymerases and a model B-family DNA polymerase.
  • To elucidate the mechanism of inhibition employed by MK886.
  • To explore the binding interactions of MK886 with Y-family DNA polymerases using computational modeling.

Main Methods:

  • Enzyme inhibition assays were performed to determine IC(50) values for MK886 against a panel of DNA polymerases.
  • Michaelis-Menten kinetic analyses and DNA binding assays were utilized to characterize the inhibition mechanism.
  • In silico docking studies were conducted to model MK886 binding to Y-family DNA polymerases.

Main Results:

  • MK886 inhibited most tested DNA polymerases with similar IC(50) values.
  • A 6- to 8-fold increased potency of inhibition was observed for human DNA polymerase iota (hpol ι), an error-prone polymerase utilizing Hoogsteen base-pairing.
  • The N-terminal extension of hpol ι partially abrogated MK886 specificity; docking revealed conserved and hpol ι-unique binding pockets.

Conclusions:

  • MK886 exhibits mixed-type inhibition of DNA polymerases, with notable specificity towards hpol ι.
  • The findings provide insights into the general mechanism of DNA polymerase inhibition by MK886.
  • Understanding these interactions could inform the development of targeted adjuvant therapies against cancer.

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