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

Keen BA, Bailey LJ, Jozwiakowski SK, Doherty AJ - Nucleic Acids Res. (2014)

Bottom Line: Here, we examined whether this mutation resulted in any changes in the molecular and cellular activities associated with human PrimPol.We also demonstrate that the decreased activity of PrimPolY89D is associated with reduced affinities for DNA and nucleotides, resulting in diminished catalytic efficiency.This mutation also reduces cell viability after DNA damage and significantly slows replication fork rates in vivo.

View Article: PubMed Central - PubMed

Affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton BN1 9RQ, UK.

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Related in: MedlinePlus

PrimPolY89D mutation is located adjacent to active site Motif I. An alignment of PrimPol protein sequences from a variety of chordates, including examples of mammals, reptiles, amphibians, birds and fish. The position of the mutated tyrosine 89 in human PrimPol is denoted by an arrow and is labelled ‘Y89’. The relative proximity of this residue to the catalytic motifs (I–III) is shown in the AEP domain. The zinc finger domain is denoted by ‘Zfn’.
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Figure 1: PrimPolY89D mutation is located adjacent to active site Motif I. An alignment of PrimPol protein sequences from a variety of chordates, including examples of mammals, reptiles, amphibians, birds and fish. The position of the mutated tyrosine 89 in human PrimPol is denoted by an arrow and is labelled ‘Y89’. The relative proximity of this residue to the catalytic motifs (I–III) is shown in the AEP domain. The zinc finger domain is denoted by ‘Zfn’.

Mentions: The active site of PrimPol is predicted to consist of three magnesium-coordinating, negatively charged residues: an aspartate at residue 114, a glutamate at residue 116 and an aspartate at residue 280 (4). Although the tyrosine at position 89 is not predicted to reside directly within the active site, it is in close proximity and therefore may play yet undetermined roles in the activities associated with these enzymes. The mutated tyrosine (Y89) is a highly conserved residue across a wide array of chordate species (Figure 1) and PolyPhen-2 prediction programme indicates that mutation of this residue would be functionally damaging (9). In addition to PrimPol, this tyrosine is also present in the related predicted primase PF14_0050 in plasmodium falciparum, so its evolutionary conservation is indicative of a significant functional residue (13).


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

Keen BA, Bailey LJ, Jozwiakowski SK, Doherty AJ - Nucleic Acids Res. (2014)

PrimPolY89D mutation is located adjacent to active site Motif I. An alignment of PrimPol protein sequences from a variety of chordates, including examples of mammals, reptiles, amphibians, birds and fish. The position of the mutated tyrosine 89 in human PrimPol is denoted by an arrow and is labelled ‘Y89’. The relative proximity of this residue to the catalytic motifs (I–III) is shown in the AEP domain. The zinc finger domain is denoted by ‘Zfn’.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231748&req=5

Figure 1: PrimPolY89D mutation is located adjacent to active site Motif I. An alignment of PrimPol protein sequences from a variety of chordates, including examples of mammals, reptiles, amphibians, birds and fish. The position of the mutated tyrosine 89 in human PrimPol is denoted by an arrow and is labelled ‘Y89’. The relative proximity of this residue to the catalytic motifs (I–III) is shown in the AEP domain. The zinc finger domain is denoted by ‘Zfn’.
Mentions: The active site of PrimPol is predicted to consist of three magnesium-coordinating, negatively charged residues: an aspartate at residue 114, a glutamate at residue 116 and an aspartate at residue 280 (4). Although the tyrosine at position 89 is not predicted to reside directly within the active site, it is in close proximity and therefore may play yet undetermined roles in the activities associated with these enzymes. The mutated tyrosine (Y89) is a highly conserved residue across a wide array of chordate species (Figure 1) and PolyPhen-2 prediction programme indicates that mutation of this residue would be functionally damaging (9). In addition to PrimPol, this tyrosine is also present in the related predicted primase PF14_0050 in plasmodium falciparum, so its evolutionary conservation is indicative of a significant functional residue (13).

Bottom Line: Here, we examined whether this mutation resulted in any changes in the molecular and cellular activities associated with human PrimPol.We also demonstrate that the decreased activity of PrimPolY89D is associated with reduced affinities for DNA and nucleotides, resulting in diminished catalytic efficiency.This mutation also reduces cell viability after DNA damage and significantly slows replication fork rates in vivo.

View Article: PubMed Central - PubMed

Affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton BN1 9RQ, UK.

Show MeSH
Related in: MedlinePlus