Richard D. Kolodner, Ludwig Institute for Cancer Research, San Diego
Richard D.
Kolodner
Cell division, Tumor biology
Bio

I am a geneticist and a biochemist. My current research program is directed at understanding how cells prevent the accumulation of mutations and genome rearrangements.
 

Our research efforts primarily use the yeast Saccharomyces cerevisiae as a model organism for basic studies, and we have applied insights from these studies to understanding the genetics of human cancer susceptibility. As a consequence, our fundamental discoveries about DNA mismatch repair and the pathways that prevent genome instability over the past several decades have proved to be central to understanding the genetics of cancer susceptibility.

I received my BS (1971) and PhD (1975) from the University of California, Irvine, and was a postdoctoral fellow at Harvard Medical School (1975-78). From 1978 to 1997 I was a faculty member at the Dana-Farber Cancer Institute and the Department of Biological Chemistry and Molecular Pharmacology at Harvard Medical School. Since 1997, I have been a member of the Ludwig Institute for Cancer Research in San Diego, where I head the Laboratory of Cancer Genetics. I am also a Distinguished Professor in the departments of Medicine and Cellular and Molecular Medicine at University of California, San Diego School of Medicine and a member of the Moores-UCSD Cancer Center, the UCSD Institute of Genomic Medicine and the Biomedical Sciences graduate program. I also serve as Head of Academic Affairs for the worldwide operations of the Ludwig Institute for Cancer Research.

I have served on numerous grant review panels and advisory boards for the National Institutes of Health, including the Board of Scientific Counselors of the National Cancer Institute, as well as on the scientific advisory boards of the MD Anderson Cancer Center, the USC-Norris Cancer Center, the University of New Mexico Cancer Center and the Stand Up 2 Cancer Foundation. In addition, I have served on the Howard Hughes Medical Institute Scientific Review Board and serve on the Scientific Review Council of the Cancer Prevention & Review Institute of Texas. I have also served on the editorial boards of a number of journals, including Cell, Molecular and Cellular Biology, the Journal of Biological Chemistry and DNA Repair and have been active in organizing several national and international scientific meetings. I have published more than 275 papers.

Education
BS, University of California, Irvine, 1971

PhD, University of California, Irvine, 1975


Achievements

National Cystic Fibrosis Foundation Postdoctoral Fellowship, 1975

NIH Postdoctoral Fellowship, 1976

ACS Junior Faculty Research Award, 1981

ACS Faculty Research Award, 1984

Special Scientific Achievement Award, Sandoz Pharmaceuticals Inc., 1994

Morse Research Award, Dana-Farber Cancer Institute, 1994

Charles S. Mott Prize, General Motors Cancer Research Foundation, 1996

Elected, Fellow of the American Academy of Microbiology, 1998

Elected, National Academy of Sciences (USA), 2000

Ernst W. Bernter Award, MD Anderson Cancer Center, 2002

Katharine Berkan Judd Award, Memorial Sloan Kettering Cancer Center, 2006

Kirk A. Landon-AACR Award for Basic Cancer Research, 2007

Elected, Fellow of the American Academy of Arts and Sciences, 2008

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Richard Kolodner lab

The major research interest of the Laboratory of Cancer Genetics, which is run jointly with Christopher Putnam, is how cells maintain the integrity of their genome. Our efforts utilize Saccharomyces cerevisiae as a model system for studying both DNA Mismatch Repair and the pathways that prevent genome rearrangements. We are also interested in applying insights from model systems to the study of genome instability in cancer.

Richard D. Kolodner, Ludwig Institute for Cancer Research, San Diego
Richard D.
Kolodner
Cell division, Tumor biology
Bio

I am a geneticist and a biochemist. My current research program is directed at understanding how cells prevent the accumulation of mutations and genome rearrangements.
 

Our research efforts primarily use the yeast Saccharomyces cerevisiae as a model organism for basic studies, and we have applied insights from these studies to understanding the genetics of human cancer susceptibility. As a consequence, our fundamental discoveries about DNA mismatch repair and the pathways that prevent genome instability over the past several decades have proved to be central to understanding the genetics of cancer susceptibility.

I received my BS (1971) and PhD (1975) from the University of California, Irvine, and was a postdoctoral fellow at Harvard Medical School (1975-78). From 1978 to 1997 I was a faculty member at the Dana-Farber Cancer Institute and the Department of Biological Chemistry and Molecular Pharmacology at Harvard Medical School. Since 1997, I have been a member of the Ludwig Institute for Cancer Research in San Diego, where I head the Laboratory of Cancer Genetics. I am also a Distinguished Professor in the departments of Medicine and Cellular and Molecular Medicine at University of California, San Diego School of Medicine and a member of the Moores-UCSD Cancer Center, the UCSD Institute of Genomic Medicine and the Biomedical Sciences graduate program. I also serve as Head of Academic Affairs for the worldwide operations of the Ludwig Institute for Cancer Research.

I have served on numerous grant review panels and advisory boards for the National Institutes of Health, including the Board of Scientific Counselors of the National Cancer Institute, as well as on the scientific advisory boards of the MD Anderson Cancer Center, the USC-Norris Cancer Center, the University of New Mexico Cancer Center and the Stand Up 2 Cancer Foundation. In addition, I have served on the Howard Hughes Medical Institute Scientific Review Board and serve on the Scientific Review Council of the Cancer Prevention & Review Institute of Texas. I have also served on the editorial boards of a number of journals, including Cell, Molecular and Cellular Biology, the Journal of Biological Chemistry and DNA Repair and have been active in organizing several national and international scientific meetings. I have published more than 275 papers.

Education
BS, University of California, Irvine, 1971

PhD, University of California, Irvine, 1975


Achievements

National Cystic Fibrosis Foundation Postdoctoral Fellowship, 1975

NIH Postdoctoral Fellowship, 1976

ACS Junior Faculty Research Award, 1981

ACS Faculty Research Award, 1984

Special Scientific Achievement Award, Sandoz Pharmaceuticals Inc., 1994

Morse Research Award, Dana-Farber Cancer Institute, 1994

Charles S. Mott Prize, General Motors Cancer Research Foundation, 1996

Elected, Fellow of the American Academy of Microbiology, 1998

Elected, National Academy of Sciences (USA), 2000

Ernst W. Bernter Award, MD Anderson Cancer Center, 2002

Katharine Berkan Judd Award, Memorial Sloan Kettering Cancer Center, 2006

Kirk A. Landon-AACR Award for Basic Cancer Research, 2007

Elected, Fellow of the American Academy of Arts and Sciences, 2008

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TEAM

Christopher
Putnam
Bio

Assistant Investigator/Assistant Professor

Nikki
Bowen
Bio

Research Technician

Eva
Goellner
Bio

Postdoctoral Fellow

Eric
Jaehnig
Bio

Postdoctoral Fellow

Sandra
Martinez
Bio

Research Technician

Katie
Pallis
Bio

Research Technician

Anjan
Srivatsan
Bio

Postdoctoral Fellow

Sara
Bell
Bio

PhD student

Sarah
Clotfelter
Bio

MS student

Yuki
Ishii
Bio

Research Associate

Binzhong
Li
Bio

Postdoctoral Fellow

Rahul
Nene
Bio

MD PhD student

Catherine
Smith
Bio

Postdoctoral Fellow

RESEARCH AREAS

Our work focuses on two projects: the mechanisms of DNA Mismatch Repair (MMR) and the pathways that prevent genome instability. Our efforts utilize Saccharomyces cerevisiae for performing biochemical, cell biological and genetic analyses of these processes. Building on our prior studies of MMR defects in cancer, we also have longstanding efforts to apply insights from our basic studies on genome instability to understanding the basis for genome rearrangements seen in cancers.

Click the links below to learn more.

DNA mismatch repair

Our laboratory has worked on basic MMR mechanisms and on the involvement of MMR defects in the development of cancer. Our prior work in S. cerevisiae led to the identification of most of the known eukaryotic MMR genes, the current models for the eukaryotic MMR pathways as well as purification and characterization of many of the eukaryotic MMR proteins. Our work also demonstrated that defects in MMR genes cause the inherited cancer susceptibility syndrome, Lynch Syndrome (also called Hereditary Non-polyposis Colorectal Carcinoma or HNPCC), that silencing of the MMR gene MLH1 underlies the majority of the sporadic MMR defective cancers and MLH1 epimutations are found in some suspected HNPCC cases.

Our most recent work on MMR has focused on four areas:

First, to provide insights into how MMR recognizes mispaired bases inside of cells, we have studied the coupling of MMR to DNA replication. In one study, we restricted the expression of the mispair recognition complex Msh2-Msh6 to specific parts of the cell cycle and showed that MMR occurs only in a short window of time after DNA replication occurs and is linked to an S-phase signal most likely produced by DNA replication itself.

In a second study, we collaborated with the Desai lab to image MMR proteins in living cells and demonstrate that MMR proteins are an integral component of replication forks. Second, we have performed genetic studies to further identify features of MMR pathways. These studies have identified an Exonuclease1-independent MMR that is dependent on the Mlh1-Pms1 endonuclease and an Exonuclease1-dependent MMR pathway that is not dependent on the Mlh1-Pms1 endonuclease function.

Third, we have purified all known MMR proteins, including Msh2-Msh6, Msh2-Msh3, Mlh1-Pms1, PCNA, RFC, RPA and DNA polymerase δ as well as Mlh1-Mlh2 and Mlh1-Mlh3 that had not been purified to homogeneity before and Exo1 that had not been purified in stable, active form before and have reconstituted Mlh1-Pms1-independent and –dependent MMR reactions in vitro.

Finally, we have used biophysical methods including X-ray Crystallography, Small Angle X-ray Scattering, Deuterium Exchange Mass Spectrometry and Surface Plasmon Resonance in combination with genetics and molecular modeling to study individual MMR proteins.

 

MMR diagram, Richard Kolodner lab, Ludwig Institute for Cancer Research

Model illustrating the known MMR proteins and their activities on different classes of mispairs.
Msh2-Msh6 and Msh2-Msh3 are mispair recognition factors. Mlh1-Pms1 is an endonuclease required for MMR that interacts with the mispair recognition factors and Mlh1-Mlh3 is a minor less well understood endonuclease. Mlh1-Mlh2 has no known function. Exo1 defines one of the redundant excision pathways that acts in MMR. PCNA, RFC, RPA and DNA polymerase d are replication proteins that act in MMR.

 

Suppression of genome rearrangements

Our laboratory works on identifying the pathways that prevent genome rearrangements.  Our prior studies in S. cerevisiae developed the first quantitative genetic assays for measuring the accumulation of gross chromosomal rearrangements, abbreviated as GCRs. This critical advance allowed us to identify the first genes known to suppress GCRs. Subsequent analysis of these genes provided many insights into how GCRs are prevented and the mechanisms that form GCRs.

Our most recent work on the suppression of GCRs has focused on four areas:

First, to more broadly analyze the ability of the genome to participate in the formation of GCRs, we developed GCR assays with breakpoint regions containing segmental duplications or a Ty1 retrotransposon (similar to mammalian LINE elements) in addition to our original GCR assays in which breakpoints were confined to occur in regions of single copy sequence. Studies with these assays have demonstrated the existence of pathways that specifically suppress GCRs mediated by duplicated sequences.

Second, we have continued to investigate mechanistic features of GCR formation. These efforts found that dicentric translocations are unstable and after breakage undergo secondary rearrangements to yield stable, complex translocations and have identified key pathways such as post-replication repair and different chromatin-remodeling pathways that prevent GCRs arising because of replication errors.

Third, to broadly identify the genes and pathways that prevent GCRs, we have implemented a novel genetic screen incorporating bioinformatics and robotic approaches to identify the majority of the genes and pathways that suppress GCRs. As a result, we identified a genetic network involving 413 genes (to date) that act to suppress GCRs vastly expanding the number of genes known to function in preventing GCRs.

Finally, because genome instability is a characteristic of many tumors, in collaboration with Dr. Sandro de Souza (formerly of Ludwig Sao Paulo) we have been mining the Cancer Genome Atlas data for defects in human homologues of the S. cerevisiae genes that suppress GCRs and have developed evidence that some of these genes are inactivated in different tumors.

 

GCR assays, Richard Kolodner lab, Ludwig Institute for Cancer Research

Diagram of some of the modified chromosomes used to detect GCRs.
Illustrated is the non-essential terminal region of each chromosome arm showing the selectable genes CAN1 and URA3 (Red), segmental duplications or Ty elements (Blue) that can mediate GCRs when present and the most telomeric essential gene (Black). Cells containing a chromosome that has lost the CAN1 and URA3 genes and has been healed by formation of a GCR become resistant to the toxic compounds canavanine and 5-fluoroorotic acid.

 

PUBLICATIONS

Putnam, CD, Hayes, TK, and Kolodner, RD. Specific pathways prevent duplication-mediated genome rearrangements. Nature.  2009; 460:984-989.

Mendillo, ML, Putnam, CD, Mo, AO, Jamison, JW, Woods, VL Jr, and Kolodner, RD. Probing DNA and ATP-mediated conformational changes in the MutS family of mispair recognition proteins using Deuterium Exchange Mass Spectrometry. J. Biol. Chem. 2010; 285:13170-13182.

Hombauer, H, Campbell, CS, Smith, CE, Desai, A, and Kolodner, RD. Visualization of Eukaryotic DNA Mismatch Repair Reveals Distinct Recognition and Repair Associated Intermediates. Cell. 2011; 147:1040-1053.

Hombauer, H, Srivatsan, A, Putnam, CD, and Kolodner, RD. Mismatch repair, but not heteroduplex rejection, is temporally coupled to replication is Saccharomyces cerevisiae. Science. 2011; 334:1713-1716.

Putnam, CD, Soltero, S, Martinez, S, Hayes, TK, Chan, J, and Kolodner, RD. Bioinformatic identification of genes suppressing genome instability. Proc. Natl. Acad. Sci. USA.  2012; 109:E3251-3259.