Faculty / Research

Daniel Bogenhagen, MD

Professor 

 

M.D., Stanford University

Postdoctoral, Carnegie Institution of Washington Department of Embryology

631-444-3068  daniel.bogenhagen@stonybrook.edu
Mitochondrial Molecular Biology

Single-base mutations and deletions in mtDNA contribute to a variety of human diseases and have been documented in a large fraction of cancers. A comprehensive understanding of the replication, repair, and expression of mtDNA is required to explain the pathological effects of these mutations. Since the 17-kB mtDNA genome encodes none of the proteins required for its own replication or transcription, mitochondrial DNA and RNA polymerases, along with a set of transcription and replication factors, must be synthesized as products of nuclear genes and imported into mitochondria. A long-term goal of this laboratory is to understand important features of nuclear-mitochondrial interactions. Our laboratory has purified, studied and, in many cases, cloned, mitochondrial regulatory proteins including both subunits of DNA polymerase g, mtRNA polymerase, mitochondrial transcription factors mtTFA and mtTFB, mtDNA ligase, mitochondrial single stranded DNA binding protein, and topoisomerase.

 

The small subunit of DNA polymerase g functions as a processivity factor for the large subunit. The large subunit contains the catalytic center of the DNA polymerase and is closely related to DNA pol I of E. coli and to HIV reverse transcriptase. Much of the toxicity of nucleoside inhibitors (eg., AZT, ddC) used in treatment of AIDS is due to inhibition of mitochondrial DNA polymerase. DNA pol g is obviously important for the sort of mutagenesis of mtDNA that is observed in some human diseases. In collaboration with the lab of Dr. Caroline Kisker of this Department, we have recently solved the structure of the small subunit. This protein shows a dramatic similarity to prokaryotic tRNA synthetases, qualifying it as a unique example of a polymerase processivity factor distinct from sliding clamps such as PCNA.

 

We have shown that DNA pol g works with mtDNA ligase in a classical base excision repair mechanism to permit repair of some types of DNA lesions. Interestingly, many of the proteins involved in base excision repair in mitochondrial are differentially-expressed variant products of genes that also supply repair factors to the nucleus. MtDNA ligase is one example of this “mitochondrial moonlighting” since it is a product of the DNA ligase III gene. We are actively studying the control of expression of these dual-function genes, since misregulation of their expression may lead to increased mutagenesis in mtDNA. Other types of lesions in mtDNA are not subject to base excision repair and appear to persist in mtDNA. We are exploring the possibility that mistakes made by the polymerase in copying damaged DNA may contribute to mutagenesis.

Recent 


Zheng, L., Zhou, M., Guo, Z., Lu,H., Qian, L., Dai, H. , Qiu, J., Yakubovskaya, E., Bogenhagen, D.F., Demple, B. and Shen, B. (2008). Human DNA2 is a mitochondrial nuclease/helicase for efficient processing of DNA replication and repair intermediates. Mol Cell 32: 325-336. Pubmed

Liu, P., Qian, L., Sung, J.-S., deSouza-Pinto, N.C., Zheng, L., Bogenhagen, D.F., Bohr, V.A., WilsonIII, D.M., Shen, B., and Demple, B. (2008). Long-Patch Base Excision DNA Repair Dependent on FEN1 in Human Cell Mitochondria, Mol. Cell. Biol. 28:4975-4987. Pubmed

Bogenhagen, D.F. Rousseau, D. and Burke, S. (2008). The Layered Structure of Human mtDNA Nucleoids. J. Biol. Chem. 283: 3665-3675. Pubmed

Watkins, J., Basu, S. and Bogenhagen, D.F. (2008). Quantitative Proteomic Analysis of Cell Cycle, Metabolic and Cytoskeletal Changes Accompanying P19 Cell Neuronal Differentiation. J. Proteome Res. 7: 328-338. Pubmed

Yakubovskaya, E., Lukin, M., Chen, Z., Berriman, J., Wall, J.S., Kobayashi,R., Kisker, C., and Bogenhagen, D.F. (2007). The EM Structure of Human DNA Polymerase Gamma Reveals a Localized Contact between the Catalytic and Accessory Subunits. EMBO J., 26: 4283-91. Pubmed

Wang, Y. and Bogenhagen, D.F. (2006). Human mtDNA Nucleoids Are Linked to Protein Folding Machinery and Metabolic Enzymes at the Mitochondrial Inner Membrane. J. Biol. Chem., 281: 25791-25802. Pubmed

Basu, S., Bremer, E., Zhou, C. and Bogenhagen, D.F. (2006) MiGenes: A Searchable Interspecies Database of Mitochondrial Proteins Curated Using Gene Ontology Annotation. Bioinformatics 22: 485-492. Pubmed

Yakubovskaya, E., Chen, Z., Carrodeguas, J.A., Kisker, C. and Bogenhagen, D.F. (2006). Functional Human Mitochondrial DNA Polymerase Gamma Forms a Heterotrimer. J. Biol. Chem. 281: 374-382. Pubmed

Pinz, K.G. and Bogenhagen, D.F. (2006). The Influence of the DNA Polymerase Gamma Accessory Subunit on Base Excision Repair by the Catalytic Subunit. DNA Repair 6: 121-128. Pubmed

 

Selected Earlier Publications


Bogenhagen, DF, Wang,Y, Shen, E and Kobayashi, R. (2003). Protein Components of Mitochondrial DNA Nucleoids in Higher Eukaryotes. Molecular and Cellular Proteomics, 2: 1205-1216. PubMed

Carrodeguas JA, Pinz KG and Bogenhagen DF. (2002). DNA binding properties of human pol GammaB. J Biol Chem. 277:50008-14. PubMed

Carrodeguas, J.A., Theis, K., Bogenhagen, D.F. and Kisker, C. (2001). Crystal Structure and Deletion Analysis Show that the Accessory Subunit of Mammalian DNA Polymerase gamma, Pol gammaB, Functions as a Homodimer. Mol. Cell 7: 43-54. Pubmed

Perez-Jannotti, R, Klein, SM and Bogenhagen, DF. (2001). Two forms of mitochondrial DNA ligase III are produced in Xenopus laevis oocytes. J. Biol. Chem. 276: 48978-48987. PubMed

Shen, EL and Bogenhagen, DF. (2001). Developmentally-Regulated Packaging of Mitochondrial DNA by the HMG-box Protein mtTFA during Xenopus Oogenesis. Nucleic Acids Res. 29: 2822-2828. PubMed

Pinz, KG and Bogenhagen, DF. (2000) Characterization of a catalytically slow AP lyase activity in DNA polymerase gamma and other family A DNA polymerases. J Biol Chem. 275:12509-14. PubMed

Carrodeguas JA, Kobayashi R, Lim SE, Copeland WC and Bogenhagen DF. (1999) The accessory subunit of Xenopus laevis mitochondrial DNA polymerase gamma increases processivity of the catalytic subunit of human DNA polymerase gamma and is related to class II aminoacyl-tRNA synthetases. Mol Cell Biol. 19:4039-46. PubMed

Bogenhagen, D.F. (1999). Repair of Mitochondrial DNA. Am. J. Hum. Genet. 64:1276-1281 Pubmed

Pinz, K.G. and Bogenhagen, D.F. (1998). Efficient Repair of Abasic Sites in DNA by Mitochondrial Enzymes. Mol. Cell. Biol. 18: 1257-1265. Pubmed