title: DNA expansions generated by human Polμ on iterative sequences.
abstract: Polµ is the only DNA polymerase equipped with template-directed and terminal transferase activities. Polµ is also able to accept distortions in both primer and template strands, resulting in misinsertions and extension of realigned mismatched primer terminus. In this study, we propose a model for human Polµ-mediated dinucleotide expansion as a function of the sequence context. In this model, Polµ requires an initial dislocation, that must be subsequently stabilized, to generate large sequence expansions at different 5'-P-containing DNA substrates, including those that mimic non-homologous end-joining (NHEJ) intermediates. Our mechanistic studies point at human Polµ residues His(329) and Arg(387) as responsible for regulating nucleotide expansions occurring during DNA repair transactions, either promoting or blocking, respectively, iterative polymerization. This is reminiscent of the role of both residues in the mechanism of terminal transferase activity. The iterative synthesis performed by Polµ at various contexts may lead to frameshift mutations producing DNA damage and instability, which may end in different human disorders, including cancer or congenital abnormalities.
authors.affiliation: Centro de Biologia Molecular Severo Ochoa, CSIC-UAM, 28049 Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Aza
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Martin
authors.forename: Raquel
authors.initials: R
authors.lastname: Juarez
authors.forename: Luis
authors.initials: L
authors.lastname: Blanco
authors.forename: Gloria
authors.initials: G
authors.lastname: Terrados
mesh_terms: D001120:Arginine / Q000737:chemistry; D059766:DNA End-Joining Repair; D019951:DNA Polymerase beta / Q000378:metabolism; D042622:DNA Repeat Expansion; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000378:metabolism*; D006639:Histidine / Q000737:chemistry; D006801:Humans; D013698:Templates, Genetic; D018911:Trinucleotide Repeats
chemical_list: D006639:Histidine; D001120:Arginine; C415367:DNA polymerase beta2; C407743:DNA polymerase mu; D019951:DNA Polymerase beta; D004259:DNA-Directed DNA Polymerase