Human DNA polymerases lambda and beta show different efficiencies of translesion DNA synthesis past abasic sites and alternative mechanisms for frameshift generation.
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.
Blanca
Giuseppina
G
Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique, 205 route de Narbonne, 31077 Toulouse Cedex, France.
Villani
Giuseppe
G
Shevelev
Igor
I
Ramadan
Kristijan
K
Spadari
Silvio
S
Hübscher
Ulrich
U
Maga
Giovanni
G
D001483:Base Sequence; D004249:DNA Damage; D019951:DNA Polymerase beta / Q000737:chemistry* / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004260:DNA Repair; D004261:DNA Replication; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism; D016368:Frameshift Mutation; D005663:Furans / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D012091:Repetitive Sequences, Nucleic Acid; D013379:Substrate Specificity; D013698:Templates, Genetic
D017931:DNA Primers; D005663:Furans; C018674:tetrahydrofuran; C415367:DNA polymerase beta2; D019951:DNA Polymerase beta; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase