Human PrimPol mutation associated with high myopia has a DNA replication defect.
Nucleic Acids Res
; 42(19): 12102-11, 2014 Oct 29.
Article
in En
| MEDLINE
| ID: mdl-25262353
ABSTRACT
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.
Full text:
1
Database:
MEDLINE
Main subject:
Point Mutation
/
DNA Primase
/
DNA-Directed DNA Polymerase
/
DNA Replication
/
Multifunctional Enzymes
/
Myopia
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Humans
Language:
En
Year:
2014
Type:
Article