Abstract
BackgroundDNA polymerase lambda (Polλ) 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 FindingsHere, we described a novel natural allelic variant of human Polλ (hPolλ) 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 Polλ 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 hPolλ 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 hPolλ.ConclusionsThe 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.
Highlights
The maintenance of genome integrity is dependent on numerous mechanisms, which notably allow fidelity of DNA replication and repair of damaged DNA [1]
These results establish that chromosomal aberrations can result from mutations in specialized DNA repair polymerases
polymerase lambda (Poll) is able to perform alignment-based gap filling for non-homologous end joining (NHEJ) in human nuclear extracts [19], and the expression in mammalian cells of a catalytically inactive form of Poll decreases the frequency of NHEJ events in response to I-Sce-I –induced double-strand breaks (DSB) [20]
Summary
The maintenance of genome integrity is dependent on numerous mechanisms, which notably allow fidelity of DNA replication and repair of damaged DNA [1]. Poll forms a Polb-like core that consists of two domains: 31 kDa polymerization domain (bearing the three conserved subdomains: fingers, palm, thumb) and 8 kDa domain [7] In agreement with their structural relationships (32% amino acid identity), the biochemical properties of Poll are partly similar to those of Polb, and suggest a role in DNA repair [8]. Poll is able to perform alignment-based gap filling for NHEJ in human nuclear extracts [19], and the expression in mammalian cells of a catalytically inactive form of Poll decreases the frequency of NHEJ events in response to I-Sce-I –induced DSB [20] All these features support a potential role for Poll in the NHEJ repair of DSB. 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)
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