Human DNA polymerases lambda and beta show different efficiencies of translesion DNA synthesis past abasic sites and alternative mechanisms for frameshift generation

Biochemistry. 2004 Sep 14;43(36):11605-15. doi: 10.1021/bi049050x.

Abstract

Human DNA polymerases (pols) beta and lambda could promote template slippage and generate -1 frameshifts on defined heteropolymeric DNA substrates containing a single abasic site. Kinetic data demonstrated that pol lambda was more efficient than pol beta in catalyzing translesion DNA synthesis past an abasic site, particularly in the presence of low nucleotide concentrations. Moreover, pol lambda was found to generate frameshifts in two ways: first, by using a nucleotide-stabilized primer misalignment mechanism, or second, by promoting primer reannealing using microhomology regions between the terminal primer sequence and the template strand. Our results suggest a molecular mechanism for the observed high in vivo rate of frameshifts generation by pol lambda and highlight the remarkable ability of pol lambda to promote microhomology pairing between two DNA strands, further supporting its proposed role in the nonhomologous end joining process.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • DNA Damage*
  • DNA Polymerase beta / chemistry*
  • DNA Polymerase beta / metabolism
  • DNA Primers / chemistry
  • DNA Repair*
  • DNA Replication*
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / metabolism
  • Frameshift Mutation*
  • Furans / chemistry
  • Humans
  • Kinetics
  • Repetitive Sequences, Nucleic Acid
  • Substrate Specificity
  • Templates, Genetic

Substances

  • DNA Primers
  • Furans
  • tetrahydrofuran
  • DNA Polymerase beta
  • DNA polymerase beta2
  • DNA-(Apurinic or Apyrimidinic Site) Lyase