Journal
EMBO JOURNAL
Volume 26, Issue 19, Pages 4283-4291Publisher
WILEY
DOI: 10.1038/sj.emboj.7601843
Keywords
DNA polymerase gamma; electron microscopy; mitochondrial DNA; processivity; replication
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Funding
- NIBIB NIH HHS [P41 EB002181, 5 P41 EB2181] Funding Source: Medline
- NIGMS NIH HHS [R01 GM029681] Funding Source: Medline
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We used electron microscopy to examine the structure of human DNA pol gamma, the heterotrimeric mtDNA replicase implicated in certain mitochondrial diseases and aging models. Separate analysis of negatively stained preparations of the catalytic subunit, pol gamma A, and of the holoenzyme including a dimeric accessory factor, pol gamma B-2, permitted unambiguous identification of the position of the accessory factor within the holoenzyme. The model explains protection of a partial chymotryptic cleavage site after residue L-549 of pol gamma A upon binding of the accessory subunit. This interaction region is near residue 467 of pol gamma A, where a disease-related mutation has been reported to impair binding of the B subunit. One pol gamma B subunit dominates contacts with the catalytic subunit, while the second B subunit is largely exposed to solvent. A model for pol c is discussed that considers the effects of known mutations in the accessory subunit and the interaction of the enzyme with DNA.
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