Abstract
Human mitochondrial DNA polymerase (Pol γ) is the sole replicase in mitochondria. Pol γ is vulnerable to nonselective antiretroviral drugs and is increasingly associated with mutations found in patients with mitochondriopathies. We determined crystal structures of the human heterotrimeric Pol γ holoenzyme and, separately, a variant of its processivity factor, Pol γB. The holoenzyme structure reveals an unexpected assembly of the mitochondrial DNA replicase where the catalytic subunit Pol γA interacts with its processivity factor primarily via a domain that is absent in all other DNA polymerases. This domain provides a structural module for supporting both the intrinsic processivity of the catalytic subunit alone and the enhanced processivity of holoenzyme. The Pol γ structure also provides a context for interpreting the phenotypes of disease-related mutations in the polymerase and establishes a foundation for understanding the molecular basis of toxicity of anti-retroviral drugs targeting HIV reverse transcriptase.
| Original language | English |
|---|---|
| Pages (from-to) | 312-324 |
| Number of pages | 13 |
| Journal | Cell |
| Volume | 139 |
| Issue number | 2 |
| DOIs | |
| State | Published - 16 Oct 2009 |
Bibliographical note
Funding Information:We thank I. Molineux for his insight, helpful discussions, and critical comments on the manuscript and K. Johnson for his long-term support, help in initiating the crystallography of Pol γ, and financial support through the National Institutes of Health (NIH; GM044613). We thank D. Bogenhagen, W. Copeland, and all members of the Y.W.Y. lab for helpful discussion. We are grateful for excellent technical support from S. Ginell and the staff at Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source, which is supported by the Department of Energy under contract DE-AC02-06CH11357. The research was supported by grants from the Welch Foundation (F-1592) and NIH (GM083703) to Y.W.Y.
Keywords
- DNA
- HUMDISEASE
