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Photo of Dr. Vilhelm A. Bohr Vilhelm A. Bohr, M.D., Ph.D., Senior Investigator
Chief, Section on DNA Repair
Oxidative DNA Damage Processing & Mitochondrial Functions Unit
Laboratory of Molecular Gerontology

Phone: 410-558-8223
Fax: 410-558-8157
E-mail: bohrv@mail.nih.gov
Biography:  Dr. Bohr received his M.D. in 1978, Ph.D. in 1987, and D.Sc. in 1987 from the University of Copenhagen, Denmark. After training in neurology and infectious diseases at the University Hospital in Copenhagen, Dr. Bohr did a postdoctoral fellowship with Dr. Hans Klenow at the University of Copenhagen, Denmark. He then worked with Dr. Philip Hanawalt at Stanford University as a research scholar from 1982-1986. In 1986, he joined the National Cancer Institute (NCI) as an investigator and become a tenured Senior Investigator in 1988. Dr. Bohr developed a research section on DNA repair at the NCI. In 1992, he moved to the National Institute on Aging to become Chief of the Laboratory of Molecular Genetics, renamed Laboratory of Molecular Gerontology in February 2001.

The Section on DNA Repair

DNA damage accumulates during life and is thought to contribute to aging and genomic instability. Therefore, defining those proteins and pathways that maintain genome stability may be critical in preventing aging and age-related degeneration. Among other projects, the Bohr group focuses on defining the molecular functions of mammalian RecQ helicases and Cockayne syndrome proteins.

Figure 1 - Three Rings Diagram We are investigating the molecular mechanisms involved in DNA repair and in genomic instability in normal, senescent and cancer cells. We are comparing the functions of all five human RecQ helicases with special emphasis towards telomere function and delineating why only three out of the five human enzymes are associated with disease (see model of where RecQs function in DNA metabolic pathways). Additionally, we are examining the role of increased DNA damage accumulation in aging and during the induction of cellular senescence. The goal is to understand the underlying mechanisms involved in DNA damage formation and it's processing as well as the changes that take place with aging that make aging cells susceptible to cancer.
Figure 1 - RecQ helicases impact all aspects of DNA metabolism, repair, recombination, replication and transcription. The boldness of the RecQ helicase font implies that that particular RecQ impacts the given DNA metabolic pathway more than other RecQs. For example, the figure shows that RECQL5 may control transcription more so than the other RecQs WRN and BLM.  
Cockayne syndrome (CS) is a rare human genetic disease, characterized by premature aging phenotypes. We are using the Cockayne syndrome (CS) mouse model to explore the nuclear-mitochondrial response network that is activated by endogenous DNA damage. The culmination of our work so far suggests that hyperactivation of PARP1 causes cellular NAD+ depletion. As a result, both SIRT1 and UCP2 expression go down, mitochondrial membrane potential and ROS levels become elevated. This leads to defective mitophagy through cleavage of the kinase PINK1. The persistent DNA damage response leads to increased energy consumption both in CS cells and in the Csbm/m mouse (see model). We’ve extrapolated our findings to two other DNA repair deficient models, XPA and AT, and see similar mitochondrial alterations. Since NAD+ depletion was central to the mitochondrial damage response, we performed rescue experiments in which we showed that PARP1 inhibitors or exogenous NAD+ precursor supplementation could ameliorate the mitochondrial changes. The implication of this work is that a nuclear DNA repair deficiency can lead to activation of a mitochondrial damage response cascade that impacts the cell’s bioenergetics. Further, we believe our findings may contribute to understanding of why neurodegeneration is seen in CS, XPA and AT patients and perhaps shed some light on future therapeutic avenues in these so far incurable diseases. Figure 2 - Mito Stress

 

Figure 2 - The mitochondrial stress response is different for cells with a DNA repair deficiency (left side, pink) versus normal cells (right side, blue). In normal cells, a mitochondrial stressor causes a loss of the mitochondrial membrane potential and accumulation of PINK1 and Parkin to the outer mitochondrial membrane. These proteins then initiate the mitophagic response to clear damaged or defective mitochondria thereby preventing cellular apoptosis. In contrast, cells with a DNA repair deficiency, that also causes activated PARP-1, have decreased NAD+ levels and high mitochondrial membrane potentials. When this type of cell encounters a mitochondrial stressor, the normal mitochondrial stress response is muted due to the high mitochondrial membrane potential which prevents mitophagy because PINK1 cannot be mobilized to the outer mitochondrial membrane. Instead these cells experience a high amount of apoptosis and cell death. In DNA repair deficient cells with activated PARP1, the aberrant mitochondrial stress response can be restored by PARP1 inhibition (PARP1i) or NAD+ supplementation (nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR)).
   
 
Photo of Dr. Vilhelm Bohr and members of the Section on DNA Repair
DNA Repair Section Oxidative DNA Damage Processing & Mitochondrial Functions Unit (left to right).
Top Row: Huiming Lu, Takashi Tadokoro, Joseph Hsu, Cindy Kasmer, Lale Dawut, Deb Croteau, Raghu Shamanna, Evandro Fang, Venkat Popuri, Will bohr
Bottom Row: Sonya Dorsey, Leslie Ferrarelli, Jane Tian, Tom Kulikowicz, Magda Misiak, Chandrika Canugovi, Chris Dunn, Morten Scheibye-Knudsen, Al May
Not Shown: Lorraine Oliver, Peter Sykora, Martin Borch Jensen
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Updated: Friday May 09, 2014