Rodney J. Rothstein, PhD

Profile Headshot

Overview

Academic Appointments

  • Professor of Genetics & Development

Administrative Titles

  • 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

Research

Harnessing the power of yeast genetics to explore biological problems

Research Interests

  • 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

Grants

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

Selected Publications

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. 479144-9159, 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.

Books:

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