Human PrimPol mutation associated with high myopia has a DNA replication defect

Keen, Benjamin A, Bailey, Laura, Jozwiakowski, Stanislaw and Doherty, Aidan J (2014) Human PrimPol mutation associated with high myopia has a DNA replication defect. Nucleic Acids Research, 42 (19). pp. 12102-12111. ISSN 0305-1048

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PrimPol is a primase-polymerase found in humans, and other eukaryotes, involved in bypassing lesions encountered during DNA replication. PrimPol employs both translesion synthesis and repriming mechanisms to facilitate lesion bypass by the replisome. PrimPol has been reported to be a potential susceptibility gene associated with the development of myopia. Mutation of tyrosine 89 to aspartic acid (PrimPolY89D) has been identified in a number of cases of high myopia, implicating it in the aetiology of this disorder. Here, we examined whether this mutation resulted in any changes in the molecular and cellular activities associated with human PrimPol. We show that PrimPolY89D has a striking decrease in primase and polymerase activities. The hydrophobic ring of tyrosine is important for retaining wild-type extension activity. We also demonstrate that the decreased activity of PrimPolY89D is associated with reduced affinities for DNA and nucleotides, resulting in diminished catalytic efficiency. Although the structure and stability of PrimPolY89D is altered, its fidelity remains unchanged. This mutation also reduces cell viability after DNA damage and significantly slows replication fork rates in vivo. Together, these findings establish that the major DNA replication defect associated with this PrimPol mutant is likely to contribute to the onset of high myopia.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Subjects: Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics > QH0447 Genes. Alleles. Genome
Depositing User: Catrina Hey
Date Deposited: 19 Nov 2014 16:14
Last Modified: 24 Mar 2017 05:43

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Project NameSussex Project NumberFunderFunder Ref
Molecular basis for repairing DNA double-strand breaks by non homologous end-joiningG0887BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCILBB/J018643/1
The role of a novel family of eukaryotic DNA polymerases in mitochondrial DNA replicationG0207BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCILBB/H019723/1
Cell cycle regulation of the NHEJ DNA double-strand break repair pathway in eukaryotesUnsetBBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCILBB/M004236/1