- Title of Seminar:
Error-Prone DNA Polymerases in Mutagenesis and
Carcinogenesis
- Period:
from December 20, 2004 to December 21, 2004, 2 days
- Site:
Maui Prince Hotel, Maui, Hawaii, U. S. A.
- Japanese Organizer:
Fumio Hanaoka (Professor, Graduate School of Frontier Biosciences, Osaka University,)
- US Organizer:
Lawrence Loeb (Professor and Director, Department of Pathology, University of Washington)
- List of Japanese-side Participants:
Yuji Masuda
Research Associate
Research Institute for Radiation Biology and Medicine, Hiroshima University
Haruo Ohmori
Associate Professor
Institute for Virus Research, Kyoto University
Susumu Nishimura
Director Emeritus
Banyu Pharmaceutical Co. Ltd., Tsukuba Research Institute
Takehiko Nohmi
Team Leader
Division of Genetics and Mutagenesis, National Institute of Health Sciences
Shunichi Takeda
Professor
Kyoto University Graduate School of Medicine
Masaru Yamaizumi
Professor
Research Institute for Developmental Biology and Medicine, Kumamoto University
Jiyang O-Wang
Team Leader
RIKEN Research Center for Allergy and Immunology
Hisaji Maki
Professor
Graduate School of Biological Sciences, Nara Institute of Science and Technology
Akio Sugino
Professor
Graduate School of Frontier Biosciences, Osaka University
Motoshi Suzuki
Assistant Professor
Nagoya University Graduate School of Medicine
Chikahide Masutani
Research Associate
Graduate School of Frontier Biosciences, Osaka University
- List of US-side Participants:
Roger Woodgate
Division Head
National Institute of Child Health and Development, National Institute of Health
Thomas Kunkel
Division Head
National Institute of Environmental Health Sciences
Christopher Lawrence
Professor
University of Rochester
Veronica Maher
Professor
Michigan State University
Errol Friedberg
Professor
University of Texas, Southwestern Medical School
Myron Goodman
Professor
University of Southern California
Joann Sweasy
Assistant Professor
Yale University
Brad Preston
Professor
University of Washington
Ashwini Kamath-Loeb
Research Associate
University of Washington
- List of Other Country Participants
Zvi Livneh
Professor
Weizman Institute (Israel)
- Agenda and Topics
- December 20th (Mon)
- Morning
- Session 1: Biochemistry of error-prone DNA polymerases
- Afternoon
- Session 2: DNA and nucleotide damage
- Session 3: DNA damage and response
- December 21st (Tue)
- Morning
- Session 4: Error-prone DNA polymerases and other polymerases
- Afternoon
- Free discussion
- Evening
- Session 5: DNA replication and polymerases
- Scientific Achievements
Within the last few years, an entire new family of DNA polymerases has been discovered and characterized mainly by investigators both in Japan and in the United States. These polymerases have been designated as the Y-family; they are found in both prokaryotes and eukaryotes, and share the capacity to copy past alterations in DNA, and exhibit low processivity, and low fidelity in copying unaltered DNA templates. Mutations in these enzymes in both prokaryotes and eukaryotes, result in altered mutation rates. The purpose of this meeting was to discuss the following questions:
- What is the association between error-prone DNA polymerases and different human cancers?
- How are error-prone DNA polymerases recruited to DNA lesions?
- Are there enzymes required for normal DNA synthesis processes?
- Are there cellular factors that prevent mutagenesis by error-prone DNA polymerases?
- Does mutagenesis result from bypass of lesions by error-prone DNA polymerase or by other factors that enhance bypass by replicative DNA polymerases?
- Would inhibition of these error-prone DNA polymerases prevent cancers or curtail tumor progression?
The outcome of this meeting could be summarized as follows:
- DNA polymerase eta is certainly involved in hereditary skin cancer. Overexpression of pol kappa is observed in lung cancer patients, but it is not clear whether the overexpression is a cause of tumor. Pol theta-deficient mouse cells show sensitivity to MMS, MNNG and cisplatin and increased apoptosis, indicating that this enzyme is involved in the prevention of genome instability.
- Mono-ubiquitination of PCNA by RAD6/RAD18 complex was found to be required for the recruitment of pol eta to the site of stalled replication site.
- There is no indication about the involvement of any error-prone DNA polymerase in normal DNA synthesis processes.
- So far, no protein factor that prevents mutagenesis by error-prone DNA polymerase has been found.
- It is pretty certain that mutagenesis results from bypass of lesions by error-prone DNA polymerase, but there is no evidence that mutagenesis is caused by other factors that enhance bypass by replicative DNA polymerases.
- It is quite possible that regulation of these error-prone DNA polymerases does prevent cancers or curtail tumor progeression.
- Other Seminar Activities (Reception, Excursion, other Meetings)
- December 19th (Sun)
- Meeting by Japanese and American organizers on how to proceed the seminar.
- December 20th (Mon)
- Banquet supported by NCI.
- December 22nd (Wed) to 24th (Fri)
- Meetings by Japanese and American organizers on the summary of seminar and discussion about how to develop the studies on this subject including collaborations between these two countries.
- Comments and Opinions
The seminar was very successful. It was quite informative, and the discussion was very intense. It is a unique meeting and extremely valuable. All the participants appreciate JSPS and NCI very much for this opportunity. We all want that this kind of meeting will be held in very near future again either in Japan or in the United States. The only asking to JSPS is that it is preferable to be able to have a banquet supported by JSPS even if the place of seminar is in the United States. It will make the seminar more comfortable.