Emory Winship Basic Research Team
Paul W. Doetsch, Ph.D.
Address
1510 Clifton Road
Rollins Research Center, Room 4013
Atlanta, GA 30322
Paul W. Doetsch, PhD, is Professor of Biochemistry, Radiation Oncology and Hematology &
Medical Oncology. He is also the Emory University School of Medicine Distinguished Chair in
Cancer Research. In addition, as Deputy Director for Basic Research for Emory Winship Cancer
Institute, he provides leadership for more than 150 cancer research faculty in five full and two
developmental scientific programs.
Dr. Doetsch is internationally recognized for his studies in the area of DNA damage, repair,
mutagenesis and genetic instability. He is the author of nearly 100 scientific publications and
recently published a textbook with colleagues Drs. Wolfram Siede and Yoke Wah Kow, DNA
Damage Recognition. Published by Taylor & Francis, Inc., the textbook covers topics from
bacteria to human cells and summarizes recent developments in our understanding of DNA
damage repair and recognition. Dr. Doetsch also has an extensive track record of service on
editorial and scientific advisory boards, NIH and American Cancer Society study sections as
well as national and international scientific committees.
For more than 20 years, Dr. Doetsch’s laboratory work has focused on the biochemistry,
molecular biology and genetics of DNA damage and repair in eukaryotes as well as the
interaction of the transcriptional machinery with DNA damage in cells. His laboratory
discovered and defined transcriptional mutagenesis. In addition, Dr. Doetsch’s recent research
has focused on understanding the interrelationships among various DNA damage management
systems and genetic instability in the development of tumors.
Dr. Doetsch earned a PhD in Biochemistry from Temple University School of Medicine in
Philadelphia. He conducted his post-doctoral work in biochemistry and molecular biology at
Dana-Farber Cancer Institute, Department of Pathology, Harvard Medical School in Boston.
Doetsch Laboratory Research
DNA Repair and Damage Tolerance
The emphasis of this area is to gain an understanding of the interrelationships between DNA repair,
damage tolerance, and other pathways that exist in eukaryotic cells for resisting genetic damage.
Eukaryotes have evolved several pathways for reversing and/or coping with DNA damage, including base
excision repair (BER), nucleotide excision repair (NER), translesion synthesis (TLS), and recombination
(REC). In general, it has previously been thought that the repair of a major part of oxidative and
alkylations DNA damage from environmental agents and endogenous sources has primarily been
mediated by the BER pathway. Using baker's yeast, Saccharomyces cerevisiae as a model eukaryotic
system to study the repair of oxidative DNA damage, we have found that there is considerable overlap
between the BER, NER, TLS and REC pathways with respect to damage processing. Mutants with both
BER and NER defects show enormous elevations in both spontaneous mutation and recombination rates.
These results indicate probably interactions between various DNA excision repair and damage tolerance
pathways in eukaryotic cells in response to exogenous and endogenous sources of oxidative and
alkylation agent-induced DNA damage. Our current studies are aimed at further dissection of the
underlying pathway interconnections between the BER, NER, TLS and REC systems operating in the
yeast nucleus and the BER and REC systems operating in yeast mitochondria which respond to and
affect the cytotoxic, mutagenic, and recombinogenic actions of certain environmental and endogenous
oxidative DNA damaging agents.
Transcriptional Mutagenesis
This group is concerned with an RNA-centric model for how new mutant proteins can arise in cells
independently of DNA replication or cell division. RNA polymerases possess the ability to transcribe past
a variety of different types of DNA damages on the template strand resulting in base misincorporations in
the RNA product. This process, which we term transcriptional mutagenesis, has been demonstrated (by
us and other groups) for a number of different in vitro transcription systems. If transcriptional mutagenesis
takes place in living cells, it could provide a major route for the generation of mutant proteins, particularly
in non-dividing cells. We are investigating the detree to which transcriptional mutagenesis occurs in the
three different model systems (bacterial, yeast and mammalian cells) possessing different DNA repair
capabilities. The goals of these studies are to define which types of genetic damage are the most potent
inducers of transcriptional mutagenesis as measured by changes in cellular phenotype. These studies
also address the likelihood of transcriptional mutagenesis in the etiology of human cancer, neurological,
and other degenerative diseases.
Alternative Excision Repair
This group focuses on understanding the alternative excision repair (AER) pathway in
Schizosaccharoymyces pombe and other organisms. AER is a DNA repair pathway initiated by a novel
endonuclease, Uve1p. Uve1p is quite diverse with respect to its ability to recognize a wide variety of
structurally diverse DNA lesions, including those caused by ultraviolet radiation, base mismatches, abasic
sites, and cisplatin lesions. Uve1p initiates the repair of these damages by making direct incisions in the
DNA backbone 5' to the lesion site. Previously, the Doetsch lab characterized Uve1p biochemically and
reconstituted a multicomponent AER pathway in vitro using purified proteins which also function in
another DNA repair pathway called base excision repair. The minimum features of AER include nicking
DNA near the site of damage (by Uve1p), removal of a small stretch of DNA containing the lesion (by the
endo-/exonuclease Rad2p), filling in the gap with new DNA (by DNA polymerase delta, RF-C and PCNA,
followed by sealing the strands (DNA ligase). Members of the Doetsch lab are currently working to refine
our basic knowledge of this pathway on biochemical, genetic and cell biological levels. Such information
should provide important insights in understanding how genetic stability is maintained and regulated in
eukaryotes and how perturbations in such systems may lead to the genetic instability phenotypes
associated with the development of mammalian cancers as well as other biological consequences of DNA
damage.