Rodney J. Rothstein, PhD
- Professor of Genetics & Development
- Vice Chair, Genetics & Development Department
- Member of Vagelos Physicians & Surgeons Office for Research Advisory Committee
I began my career interested in mechanisms of genetic recombination and chose to use yeast as a model system since I could combine genetic and molecular biological tools that were rapidly being developed in the ‘70s and ‘80s. Early on we showed that plasmids containing double-strand DNA breaks were repaired using homologous genomic sequences, which lead directly to genetic engineering, gene disruption and later to the double-strand break repair model. Using the tools that we developed, I next turned my attention to both study and search for genes involved in genome stability. We examined many of the central genes involved in genetic recombination (RAD52, RAD51, RAD1, RAD10 etc.) and also discovered new key players in this process, including TOP3, SGS1, the Shu complex and IRC genes. Since DNA repair is essential for preserving genome integrity in all organisms, it is not surprising that most of these genes are evolutionarily conserved. Several years ago, using fluorescently tagged proteins, we developed yeast strains that allow us to follow events from the initiation of the damage to its repair. These strains allow us to study the movement of chromosomes and to determine their spatiotemporal relationships during the DNA damage response, uncovering the inherent choreography of this process. The lab is also interested in using the power of yeast genetic screens to identify new connections between cellular pathways. By overexpressing a protein from one pathway, we look for genetic interactions with mutations in another pathway that cause a “synthetic” effect using colony growth as a metric. As an example, we have found new connections in the secretory pathway in a collaboration with Elizabeth Miller and Randy Schekman. We are also using yeast as a model to study cancer and cancer predisposition. We are especially interested in gene overexpression, an underexploited area of cancer biology. We find that almost all of the pathways identified in our yeast screens are conserved in mammalian cells. We have on-going collaborations with many members of my department as well as the Cancer Center, including Alberto Ciccia, Chao Lu, Zhiguo Zhang, Dawn Hershman and Gary Schwartz to exploit our yeast findings in mammalian cells. During this COVID-19 pandemic, we have turned our attention to using our yeast expertise to explore the way SARS-CoV-2 viral proteins affect host pathways. We have at our disposal humanized yeast strains containing human proteins with which viral proteins interact. We have outstanding colleagues, including Vincent Racaniello, with whom I am collaborating on this project. Finally, I am committed to the training and mentoring of students and post-docs. For the past 35 years at Columbia University Medical Center, I have trained 22 PhD students including 3 URMs (with 2 more PhD students in progress, one of whom is a URM) and 22 post-docs, many of whom are professors at various stages in their careers. Some are involved in the biotechnology industry, patent law or science filmmaking. More than 30 undergraduates have passed through my lab on their way to graduate or medical school.
Credentials & Experience
Education & Training
- BS, 1969 Biology, Chemistry, University of Illinois at Chicago
- PhD, 1975 Genetics, University of Chicago
- Fellowship: 1977 University of Rochester School of Medicine & Dentistry
- Fellowship: 1979 Cornell University - Ithaca
Honors & Awards
1969 Graduation with honors - University of Illinois, Chicago.
1976 - 1978 PHS Individual National Research Service Award
1984 - 1988 Member of the National Science Foundation Advisory Panel for Eukaryotic Genetic Biology.
1985 - 1997 Member of Editorial Board of CURRENT GENETICS.
1986 - 1990 Irma T. Hirschl Career Scientist
1986 - 1991 American Heart Association Established Investigator
1988 - 1991 Member of the Genetics Society of America Meeting Program Committee
1988 - 1993 Member of Editorial Board of Molecular and Cellular Biology
1988 - 1993 Member of the Damon Runyon - Walter Winchell Cancer Fund Scientific Advisory Committee
1989 - 1990 Member of 3 Special Study Sections for the Genome Project at NIH
1991 - 1993 Co-chairman (1991) and Chairman (1993) FASEB Summer Research Conference on Genomic Rearrangements and Genetic Recombination
1991 - 1992 Member of the Editorial Board of Genetica
1992 - 1994 Genetics Society of America Yeast Program Committee Member-at-large
1993 - 1995 Member of the National Science Foundation Advisory Panel for the MCB/NSF Young Investigator Awards
1993 - 1997 Member of the National Advisory Council for Human Genome Research of NIH
1995 - 1999 Member of Editorial Board of Genome Research
1997 Distinguished Alumnus, University of Illinois - Chicago, Department of Biology
1999 - 2000 Chair of Division X, Molecular, Cellular & General Biology of Eukaryotes, of the American Society of Microbiology
2001 Erasmus Lecture, Erasmus University Rotterdam, Netherlands
2002 Co-chair Keystone Symposium on Molecular Mechanisms in DNA Replication & Recombination
2002 - pres. Member of Editorial Board of Genes & Genetic Systems
2003 - pres. Associate Editor of DNA Repair
2004 - 2007 Member of the Israel Cancer Research Fund Scientific Review Panel
2004 - 2010 Genetics Society of America Yeast Program Committee
2005 - 2015 NIH MERIT Award (GM50237)
2005 Herbert Stern Lecture, UC San Diego, CA
2005 - 2009 Member of the Scientific Advisory Board of the European Commission Integrated Project on DNA Repair
2006 Gregor Mendel Lecture, Mendel’s Abbey, Brno, Czech Republic
2007 - pres. Fellow of the American Academy of Microbiology
2008 Co-chair FASEB Summer Research Conference on Yeast Chromosome Structure, Replication and Segregation
2008 John M. Lewis Memorial Lecture - Columbia University Medical Center, New York
2008 - pres. Fellow of the American Association for the Advancement of Science
2009 Edward Novitski Prize of the Genetics Society of America
2010 Member of MGC Study Section at NIH
2010 Giovanni Magni lecture sponsored by Fondazione Buzzati-Traverso, Milan, Italy
2011 - pres. Fellow of the American Academy of Arts & Sciences
2012 Doctor Honoris Causa in Medicine from Umeå University, Sweden
2014, 2019 Reviewer for Howard Hughes Medical Institute
2014, 2016 Co-organizer of Japanese 3R (Replication, Recombination & Repair) meeting
2015 - pres. Member of the National Academy of Sciences
2015, ’16, ‘18Ad hoc member of Pre- and Postdoc and MIRA Study Sections at NIH
2016 Genetics Society of America-sponsored Yeast Meeting: Winge-Lindegren lecture
2016 Inventor of the Year - New Jersey Inventors Hall of Fame
2017-2020 Member, Advisory Council for Institute of Quantitative Biosciences, The University of Tokyo
2019 – pres. NIH Pioneer Award Stage 1 reviewer
2019 Reviewer for Okinawa Institute of Science & Technology, Japan
2019 Keynote address at the IFOM, CRUK & MSKCC Retreat, Sardinia, Italy
2019 – pres. Member of NAS Award in Molecular Biology selection committee
Harnessing the power of yeast genetics to explore biological problems
- Yeast genetic and cell biological approaches to understand the cellular response to DNA damage
- Understanding the mechanisms of genetic recombination
- Genomic approaches to understand the control of genome stability in yeast
- Genomic approaches to understand the control of genome stability in normal & cancer cells
- Investigating SARS-CoV-2 viral-host protein interactions during viral replication
MECHANISMS OF RECOMBINATION STIMULATED BY 3 -OVERHANGS, 5 -OVERHANGS OR BLUNT ENDS (Private)
Nov 14 2019 - Nov 13 2021
MOLECULAR MECHANISMS UNDERLYING DNA DOUBLE-STRAND BREAK AND CROSSLINK REPAIR (Federal Gov)
Jul 1 2016 - Aug 31 2021
CENTERS FOR CANCER SYSTEMS THERAPEUTICS (CAST) (Federal Gov)
Aug 8 2016 - Jul 31 2021
MECHANISM OF SPONTANEOUS AND DSB-INDUCED REPAIR (Federal Gov)
Sep 1 2015 - Aug 31 2019
YEAST CHROMATIN STRUCTURE AND FUNCTION (Federal Gov)
Jan 1 2015 - Dec 31 2018
GENETICS OF THE FORMATION OF REPAIR & RECOMBINATION FOCI (Federal Gov)
Jan 1 2003 - Feb 29 2016
DEVELOPING A NEW PARADIGM TO DISCOVER NOVEL BREAST CANCER DRUG TARGETS (NY State Gov)
Sep 1 2013 - Aug 31 2015
IN VIVO CHOREOGRAPHY OF DNA MOLECULES AND REPAIR PROTEINS DU RING SEARCH FOR HOMOLOGY (Private)
Jan 1 2010 - Dec 31 2011
MECHANISTIC INSIGHTS INTO THE SHU COMPLEX AND SGS1 IN DNA RE PAIR AND REPLICATION (Federal Gov)
Aug 1 2009 - Jun 30 2011
Rothstein, R.J. Deletions of a tyrosine tRNA in Saccharomyces cerevisiae. Cell 17: 185-190, 1979.
Orr-Weaver, T., Szostak, J.W. and Rothstein, R.J. Yeast transformation: A model system for the study of recombination. Proc. Natl. Acad. Sci. USA 78: 6354-6358, 1981.
Szostak, J.W., Orr-Weaver, T.L., Rothstein, R.J. and Stahl, F.W. The double-strand-break model for genetic recombination. Cell 33: 25-35, 1983.
Rothstein, R.J. One-step gene disruption in yeast. In: Methods in Enzymology, Vol. 101, R. Wu, L. Grossman and K. Moldave, Eds., Academic Press, New York, pp. 202-211, 1983.
Thomas, B. and Rothstein, R. Elevated recombination rates in transcriptionally active DNA. Cell 56: 619-630, 1989.
Wallis, J.W., Chrebet, G., Brodsky, G., Rolfe, M. and Rothstein, R. A hyper-recombination mutation in Saccharomyces cerevisiae identifies a novel eukaryotic topoisomerase. Cell 58: 409-419, 1989.
Thomas, B. and Rothstein, R. The genetic control of direct repeat recombination in Saccharomyces: The effect of rad52 and rad1 on recombination at GAL10, a transcriptionally regulated gene. Genetics 123: 725-738, 1989.
Gangloff, S., McDonald, J. P., Bendixen, C., Arthur, L. and Rothstein, R. The yeast type I topoisomerase Top3 interacts with Sgs1, a DNA helicase homolog: a potential eukaryotic reverse gyrase. Molec. Cell. Biol. 14: 8391-8398, 1994.
Mortensen, U.H., Bendixen, C., Sunjevaric, I. and Rothstein, R. DNA strand annealing is promoted by the yeast Rad52 protein. Proc. Natl. Acad. Sci. 93: 10729-10734, 1996.
Zou, H. and Rothstein, R. Holliday junctions accumulate in replication mutants via a RecA homolog-independent mechanism. Cell 90: 87-96, 1997
Erdeniz, N., Mortensen, U.H. and Rothstein, R. Cloning-free PCR-based Allele Replacement Methods. Genome Res. 7: 1174-1183, 1997.
Zhao, X., Muller, E.G.D. and Rothstein, R. A suppressor of two essential checkpoint genes identifies a novel protein that negatively affects dNTP pools. Molecular Cell 2: 329-340, 1998.
Lisby, M., Rothstein, R. and Mortensen, U.H. Rad52 forms DNA repair and recombination centers during S phase. Proc. Natl. Acad. Sci. USA 98: 8276-8282, 2001.
Lisby, M., Barlow, J.H., Burgess, R.C. and Rothstein, R. Choreography of the DNA damage response: spatiotemporal relationships among checkpoint and repair proteins. Cell 118: 699-713, 2004.
Shor, E., Weinstein, J. and Rothstein, R. A genetic screen for top3 suppressors in Saccharomyces cerevisiae identifies SHU1, SHU2, PSY3 and CSM2: Four genes involved in error-free DNA repair. Genetics 169: 1275-1289, 2005.
Lisby, M. and Rothstein, R. The cell biology of mitotic recombination in Saccharomyces cerevisiae. In: Topics in Current Genetics - Molecular Genetics of Recombination (A. Aguilera and R. Rothstein, eds.), Springer-Verlag, Berlin, pp. 317-333, 2007.
Alvaro, D.A., Lisby, M. and Rothstein, R. Genome-wide analysis of Rad52 foci reveals diverse mechanisms impacting recombination. PLoS Genetics 3: 2439-2449, 2007 (doi:10.1371/journal.pgen.0030228).
Barlow, J.H., Lisby, M. and Rothstein, R. Differential regulation of the cellular response to DNA double-strand breaks in G1. Molecular Cell 30: 73-85, 2008.
Dittmar, J.C., Reid, R.J.D. and Rothstein, R. ScreenMill: A freely available software suite for growth measurement, analysis and visualization of high-throughput screen data. BMC Bioinformatics 11: 353, 2010.
Reid, R.J.D., González-Barrera, S., Sunjevaric, I., Alvaro, D., Ciccone, S., Wagner, M. and Rothstein, R. Selective ploidy ablation, a high-throughput plasmid transfer protocol, identifies new genes affecting topoisomerase I–induced DNA damage. Genome Research 21: 477-486, 2011.
Miné-Hattab, J. and Rothstein, R. Increased chromosome mobility facilitates homology search during recombination. Nature Cell Biol., 14: 510–517, 2012.
Dittmar, J.C., Pierce, S., Rothstein, R. and Reid, R.J.D. Physical and genetic interaction density reveals functional organization and informs significance cutoffs in genome-wide screens. Proc Natl Acad Sci USA, 110: 7389-7394, 2013.
Jasin, M. and Rothstein, R. Repair of Strand Breaks by Homologous Recombination. Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a012740, 2014.
Symington, L.S., Rothstein, R. and Lisby, M. Mechanisms and regulation of mitotic recombination in Saccharomyces cerevisiae. Genetics, 198: 795-835, 2014.
Lisby, M. and Rothstein, R. Cell biology of mitotic recombination. Cold Spring Harb Perspect Biol 7:a016535, 2015.
Reid, R.J.D., Du, X., Sunjevaric, I., Rayannavar, V., Dittmar, J., Bryant, E., Maurer, M. and Rothstein, R. A synthetic dosage lethal genetic interaction between CKS1B and PLK1 is conserved in yeast and human cancer cells. Genetics 204: 807–819, 2016.
Smith, M.J. and Rothstein, R. Poetry in motion: Increased chromosomal mobility after DNA damage. DNA Repair 56: 102-108, 2017.
Miné-Hattab, J., Recamier, V., Izeddin, I., Rothstein, R., Darzacq, X. Multi-scale tracking reveals scale-dependent chromatin dynamics after DNA damage. Mol Biol Cell. E17-05-0317. doi: 10.1091, 2017.
Billon, P., Bryant, E.E., Joseph, S.A., Nambiar, T.S., Hayward, S.B., Rothstein R. and Ciccia, A. CRISPR-mediated base editing enables efficient disruption of eukaryotic genes through induction of STOP codons. Molec. Cell 67: 1068-1079, 2017.
Smith, M.J., Bryant, E.E. and Rothstein, R. Increased chromosomal mobility after DNA damage is controlled by interactions between the recombination machinery and the checkpoint. Genes & Dev. 32: 1242-1251. doi: 10.1101/gad.317966.118, 2018.
Oh, J., Lee, S.J., Rothstein, R. and Symington, L.S. Xrs2 and Tel1 independently contribute to MR-mediated DNA tethering and replisome stability. Cell Reports 13: 1681-1692, 2018.
Šuštić, T., van Wageningen, S., Bosdriesz, E., Reid, R.J.D., Dittmar, J., Lieftink, C., Beijersbergen, R.L., Wessels, L.F.A. , Rothstein, R. and Bernards, R. A role for the Unfolded Protein Response stress sensor ERN1 in regulating the response to MEK inhibitors in KRAS mutant colon cancers. Genomic Medicine 27: 90, 2018.
Bryant, E.E., Šunjevarić, I., Berchowitz, L., Rothstein, R. and Reid, R.J.D. Rad5 dysregulation drives hyperactive recombination at replication forks resulting in cisplatin sensitivity and genome instability. Nucleic Acids Res. 47: 9144-9159, 2019.
Smith, M.J., Bryant, E.E., Joseph, F.J. and Rothstein, R. DNA damage triggers increased mobility of chromosomes in G1 phase cells. Molec. Biol. Cell 30: 2620–2625, 2019.
Aguilera, A. and Rothstein, R., editors. Topics in Current Genetics - Molecular Genetics of Recombination, Springer-Verlag, Berlin, 2007.
Rothstein, R., Forward for Weitzman, J. and Weitzman, M. 30-Second Genetics: The 50 Most Revolutionary Discoveries in Genetics, Each Explained in Half a Minute, Ivy Press, Brighton, UK, 2017