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Open Access item Characterization of a Natural Mutator Variant of Human DNA Polymerase l which Promotes Chromosomal Instability by Compromising NHEJ
García, Miguel Ángel
Kunkel, Thomas A.
|Keywords:||DNA Polymerase Lambda, Chromosomal Instability|
|Publisher:||Public Library of Science|
|Abstract:||Background: DNA polymerase lambda (Poll) is a DNA repair polymerase, which likely plays a role in base excision repair
(BER) and in non-homologous end joining (NHEJ) of DNA double-strand breaks (DSB).
Principal Findings: Here, we described a novel natural allelic variant of human Poll (hPoll) characterized by a single
nucleotide polymorphism (SNP), C/T variation in the first base of codon 438, resulting in the amino acid change Arg to Trp.
In vitro enzyme activity assays of the purified W438 Poll variant revealed that it retained both DNA polymerization and
deoxyribose phosphate (dRP) lyase activities, but had reduced base substitution fidelity. Ectopic expression of the W438
hPoll variant in mammalian cells increases mutation frequency, affects the DSB repair NHEJ pathway, and generates
chromosome aberrations. All these phenotypes are dependent upon the catalytic activity of the W438 hPoll.
Conclusions: The expression of a cancer-related natural variant of one specialized DNA polymerase can be associated to
generic instability at the cromosomal level, probably due a defective NHEJ. These results establish that chromosomal
aberrations can result from mutations in specialized DNA repair polymerases.|
|Description:||PLoS ONE 4(10): e7290.|
|Publisher version (URL):||10.1371/journal.pone.0007290|
|Appears in Collections:||(CBM) Artículos|
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