of Work: The nuclear genome is under constant attack from DNA damaging agents. Damaging agents such as cisplatinin and nitrogen mustard cause interstrand crosslinks in DNA that presents a difficult problem for replication and must be repaired for faithful replication and viability of the cell. A necessary step in repair of DNA crosslinks is the resynthesis after removal of the damaged DNA. It has been shown that most polymerases specialize in either replication of the genome or repair synthesis. We have discovered a new DNA polymerase gene from human that takes part in the repair of interstrand crosslinks. We have cloned the cDNA for the 8th human DNA polymerase, DNA polymerase q. The human cDNA encodes a putative DNA polymerase of 1762 amino acids with a calculated molecular weight of 198 kDa. The derived protein sequence is homologous to the Drosophila melanogaster mus308 protein product, a putative DNA polymerase-helicase involved in repair of interstrand crosslinks. The C-terminal region contains the canonical DNA polymerase motifs A, B and C found in the family A type of DNA polymerases which include E. coli polymerase I. The N-terminal region contains a putative ATP binding domain but not motifs for a helicase. The N-terminal half of the protein also contains a putative 3-5 exonuclease region. The presence of these three activities in the same protein prompt us to suggest a model where this enzyme unwinds the DNA strands to the site of the crosslink, completely digest one of the strands across the covalent crosslinked agent with its exonuclease function and resynthesis over the bulky adduct on the template strand. Finally, the gene was mapped by radiation hybrid analysis to chromosome 3q within an interval flanked by proximal marker D3S1303 and distal marker D3S3576 and, based on proximity to a gene that has been mapped cytogenetically, within band 3q13.31. The genetic locus of this gene may be a frequent target of mutational inactivation in individuals with genetic diseases in which DNA repair defects and/or predisposition to cancer are hallmarks. - Human Genome, Chromosome mapping, cDNA cloning Baculovirus, DNA repair, DNA replication Cisplatinin

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National Institute of Environmental Health Sciences (NIEHS)
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Burgers, P M; Koonin, E V; Bruford, E et al. (2001) Eukaryotic DNA polymerases: proposal for a revised nomenclature. J Biol Chem 276:43487-90