Gerald R. Smith

Appointments and Affiliations

Fred Hutchinson Cancer Research Center
Basic Sciences Division
Member, Appointed: 1985
University of Washington
School of Medicine
Genome Sciences and Pathology
Affiliate Professor, Appointed: 1983
Professional Headshot of Gerald R. Smith

Mailing Address

Fred Hutchinson Cancer Research Center
1100 Fairview Ave. N.
P.O. Box 19024
Seattle, Washington 98109-1024
United States


Phone: (206) 667-4438
Fax: (206) 667-6497


Ph.D., Massachusetts Institute of Technology, Biology, 1970.
B.S., Cornell University, Microbiology, 1966.

Research Interests

Recombination and DNA Break Repair: Mechanism and Control

Genetic recombination plays a crucial role in the maintenance of chromosomal integrity and the generation of genetic diversity. During mitotic growth of cells, faithful repair of DNA double-strand breaks (DSBs) requires homologous recombination. Failure to repair DSBs is often lethal, as essential genes can be lost. During meiosis, recombination plays an important role in the proper segregation of chromosomes and the formation of viable sex cells. Aberrancies in recombination thus produce chromosomal losses and rearrangements, such as deletions and translocations, and can result in birth defects or cancers. Understanding the molecular mechanism of recombination will give us insight into the causes of these diseases and possibly ways of predicting or preventing them; it will also help create new cell lines and mutant organisms by gene targeting. Common features of recombination in model organisms, including easily studied microorganisms, aid identifying human genes for recombination and DSB repair, which may be altered in specific diseases such as cancer.

Our lab's goals are to elucidate how recombination and DSB repair are accomplished and how they are regulated to occur at the proper place and time. Our research is focused on meiotic recombination in the fission yeast Schizosaccharomyces pombe and on the major (RecBCD) pathway of recombination in the bacterium Escherichia coli. In both organisms we approach this problem genetically, by analyzing mutants altered in the process, and biochemically, by studying the enzymes and special DNA sites (hotspots) that promote recombination and repair. These approaches are greatly facilitated by the advanced genetics and biochemistry of these microorganisms.

Meiotic Recombination in S. pombe

By a combination of genetics, microscopy, and biochemistry, we have outlined a pathway of proteins promoting meiotic recombination, which we divide into three stages: chromosome movement and pairing (called "horsetailing" and "bouquet" formation), DSB formation, and DSB repair. We have placed dozens of gene products into these stages and identified two central DNA intermediates of recombination – DSBs and Holliday junctions (HJs). Our genome-wide analyses of DSBs confirm our previous mapping of DSBs to hotspots of recombination; these results will help us find the chromosomal determinants of these hotspots. We are currently attempting to map HJs genome-wide, using procedures that should be applicable to any species.

We have found that DSBs at hotspots are repaired primarily with the sister, independent of Dmc1, whereas DSBs in DSB-poor (cold) regions are repaired primarily with the homolog dependent on Dmc1. Thus, despite the presence of strong DSB hotspots, there is a nearly uniform frequency of crossovers along chromosomes, a phenomenon called “crossover invariance.” Single HJs predominate instead of the double HJs usually seen in budding yeast. Our current research has revealed additional ways in which recombination differs in these two yeasts. For example, we have found roles for RNAi components, not present in budding yeast, and a histone modifying enzyme in the repression of DSB formation at recombinationally silent centromeres; we are now determining the molecular basis of this repression. We have found that palindromic DNA, a frequent feature in the human genome, confers a recombination hotspot independent of the major DSB-forming protein Rec12 (Spo11 homolog). Determining the mechanism of homologous and non-homologous recombination in S. pombe will aid studies of the mechanism in human cells.

DNA Break Repair in E. coli

We are studying the complex RecBCD enzyme and its control by the recombination hotspot Chi (5' GCTGGTGG 3'). RecBCD has multiple activities on DNA, including DNA unwinding and DNA hydrolysis. Using mutant RecBCD enzymes and electron microscopy, we have found that RecBCD unwinds DNA by producing a growing ss DNA loop through the combined action of a fast helicase (RecD) and a slower ss DNA translocase (RecB). Upon encountering Chi, RecBCD enzyme is changed such that it produces a 3' ss DNA end onto which it loads RecA strand-exchange protein; the physical basis of Chi's regulation of RecBCD is incompletely understood. We isolated novel classes of recBCD mutants whose properties led us to propose a "signal transduction cascade" model, in which RecC recognizes Chi and signals RecD to stop unwinding DNA; RecD then signals RecB to cut the DNA and to begin loading RecA. Consistent with this model, we found that RecBCD undergoes dramatic conformational changes upon binding DNA and again upon encountering Chi. We are testing this model further with a combination of genetics, enzymology, and single-molecule fluorescence microscopy. Most recently, we unexpectedly found that Chi’s activity strongly depends on the surrounding nucleotide sequences, which may reflect the ease with which RecBCD cuts DNA near Chi. RecBCD is an excellent example of a complex "protein machine"; understanding the mechanism and control of RecBCD will aid studies of other such machines, including those acting in replication and transcription.

Additional Experience

  • Faculty of 1000 Prime, section on Nuclear Structure & Function, 2002-present
  • College of CSR Reviewers, NIH, 2010-present
  • Study sections and site visit advisory committees, NIH, 1990-2016 (intermittent)
  • Board of Directors, Genetics Society of America, 2001-2004
  • Scientific Advisory Board, Damon Runyon-Walter Winchell Cancer Research Fund, 1993-1998
  • Editorial Boards (Molecular and General Genetics, Journal of Bacteriology, Journal of Molecular Biology, Genetics), 1983-2010
  • Scientific meeting organization: FASEB Conference on Genetic Recombination and Genome Rearrangements, Chair 1987, Session chair, 1991-1999
  • International Congress of Genetics, Symposium organizer, 1998
  • Gordon Conference on Meiosis, Session chair, 1994, 1998
  • International Fission Yeast Meeting, Session chair, 1999, 2002, 2004, 2007, 2009, 2011
  • EMBO Workshop on Meiosis, Session chair, 2003
  • FASEB Conference on Biological Impact of Alternatively Structured DNA, Session Chair, 2008, 2010


French: Reading (Fluent), Writing (Basic), Speaking (Fluent)


American Association for the Advancement of Science
American Society of Microbiology
Genetics Society of America

Honors and Awards

2015, Elected Fellow, American Academy of Microbiology (AAM)
2008, Elected Fellow, American Association for the Advancment of Science (AAAS)
1999-1999, Senior International Fellow, NIH Fogarty Center, Imperial Cancer Research Fund (London)
1999-1999, Research Travel Grant Awardee, Burroughs Wellcome Fund, Imperial Cancer Research Fund (London)
1980-1985, Research Career Development Awardee, National Institutes of Health, University of Oregon and Fred Hutchinson Cancer Research Center
1973-1975, International Postdoctoral Fellow, Swiss National Science Foundation, University of Geneva
1970-1973, Postdoctoral Fellow, Helen Hay Whitney Foundation, University of California at Berkeley and University of Geneva
1966-1970, Predoctoral Fellow, National Science Foundation, Massachusetts Institute of Technology
1962-1962, Finalist, Westinghouse Science Talent Search

Previous Positions

1989-2001, Affiliate Professor, University of Washington, Genetics and Pathology
1983-1989, Affiliate Associate Professor, University of Washington, Genetics and Pathology
1982-1985, Associate Member, Fred Hutchinson Cancer Research Center, Basic Sciences Division
1980-1982, Associate Professor, University of Oregon, College of Arts and Sciences (CAS), Biology, Institute of Molecular Biology
1975-1982, Research Associate, University of Oregon, College of Arts and Sciences (CAS), Biology, Institute of Molecular Biology
1975-1980, Assistant Professor, University of Oregon, College of Arts and Sciences (CAS), Biology, Institute of Molecular Biology
1972-1975, Postdoctoral Fellow, University of Geneva, Molecular Biology, Laboratory of Dr. Harvey Eisen
1970-1972, Postdoctoral Fellow, University of California, Berkeley, Biochemistry, Laboratory of Dr. Bruce Ames


  • National Institute of General Medical Sciences: R35 GM118120 Molecular Analysis of Genetic Recombination and DNA Break Repair, 2016-2021.
  • National Institute of General Medical Sciences: R01 GM32194 Molecular Mechanisms of Genetic Recombination, 1983 to 2016.
  • National Institute of General Medical Sciences: R01 GM31693 Molecular Analysis of Hotspots of Genetic Recombination, 1980 to 2016.
  • Bill & Melinda Gates Foundation: Anti-TB Drugs that limit Evolution of Resistance, 2009 to 2010.
  • R03AI083736: R03 AI083736 Novel Antibacterial Drugs Targeting DNA Repair Enzymes, 2009 to 2011.
  • Fred Hutchinson Cancer Research Center/ Synergy fund: DNA Break Repair in Helicobacter pylori: Pilot Studies for a New Class of Broad-range Antibiotics, 2007 to 2008.

Recent Publications

In Press
Ellermeier C, Higuchi EC, Phadnis N, Holm L, Geelhood JL, Thon G, Smith GR.  2010.  RNAi and heterochromatin repress centromeric meiotic recombination.. Proceedings of the National Academy of Sciences of the United States of America. 107(19):8701-5. Abstract

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