Susan M Rosenberg, Ph.D.
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Positions
- Ben F. Love Chair in Cancer Research
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Baylor College of Medicine
- Professor
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Molecular and Human Genetics
Baylor College of Medicine
- Professor
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Biochemistry & Molecular Biology
Baylor College of Medicine
- Professor
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Molecular Virology & Microbiology
Baylor College of Medicine
- Leader
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Mechanisms in Cancer Evolution Program
Dan L Duncan Comprehensive Cancer Center
Baylor College of Medicine
- Professor
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Graduate Program in Genetics and Genomics
Baylor College of Medicine
- Professor
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Graduate Program in Cancer & Cell Biology
Baylor College of Medicine
- Professor
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Graduate Program in Development, Disease Models & Therapeutics
Baylor College of Medicine
- Professor
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Graduate Program in Chemical, Physical & Structural Biology
Baylor College of Medicine
- Professor
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Graduate Program in Systems, Synthetic, and Physical Biology
Rice University
Education
- BA from State University of New York
- Potsdam
- PhD from University of Oregon
- Eugene
- Post-Doctoral Fellowship at University of Paris VII
- Paris, France
- Post-Doctoral Fellowship at University of Utah School of Medicine
- Salt Lake City
- Post-Doctoral Fellowship at National Cancer Institute
- Frederick
Honors & Awards
- NIH Director’s Pioneer Awards 2020 & 2009
- Science Magazine, Senior Editorial Board
- WM Keck Foundation Medical Research Award
- American Association for the Advancement of Science, Fellow
- American Academy of Microbiology
- Ben F. Love Chair in Cancer Research
- Biosphere and Humanity Medal, Russian Academies of Medicine and Science
- Cullen Endowed Professor in Molecular Genetics
- The Genetics Society of Canada Young Scientist Award
- The Eli Lilly/National Cancer Institute of Canada William Rawls Prize
- Michael E. DeBakey Excellence in Research Award
- Recipient, 2014, 2001
- Baylor College of Medicine Student Awards for Graduate Teaching Excellence
- Recipient, 2015, 2008, 2006, 2001, 2000
Professional Interests
- Molecular mechanisms of genome instability
- Stress-induced mutagenesis
- Cancer
- Antibiotic resistance
- Spontaneous DNA damage
Professional Statement
Genome Instability in Evolution, Antibiotic Resistance and CancerSTRESS-INDUCED MUTAGENESIS: For 50 years the world believed that mutations occur at random. The discovery of stress-induced mutagenesis has changed ideas about mutation and evolution and revealed mutagenic programs that differ from standard spontaneous mutagenesis in rapidly proliferating cells. The stress-induced mutations occur during growth-limiting stress and can include adaptive mutations that allow growth in the otherwise growth-limiting environment. We are elucidating molecular mechanisms by which these mutations form in E. coli using a variety of genetic, molecular, genomic, and whole-genome-sequencing approaches. We discovered that the normally high-fidelity mechanism of DNA double-strand-break repair is switched to a mutagenic version of that mechanism, using a special error-prone DNA polymerase, specifically when cells are stressed, under the control of two cellular stress responses. The stress responses increase mutagenesis specifically when cells are maladapted to their environments, i.e. are stressed, potentially accelerating evolution. Stress-induced mutation mechanisms may provide important models for genome instability underlying some cancers and genetic diseases, resistance to chemotherapeutic and antibiotic drugs, the pathogenicity of microbes and many other important evolutionary processes. We are interested in molecular mechanisms that drive evolution.
ANTIBIOTIC-RESISTANCE MUTATION: Some mutations that confer antibiotic-resistance form by mechanisms with similarities to recombination-dependent stress-induced mutagenesis described above. We are examining the mechanisms by which these mutations form.
SPONTANEOUS DNA DAMAGE: We created E. coli cells that fluoresce green when their DNA is damaged, and are using flow cytometry to quantify and recover green cells with spontaneous DNA damage. With this direct, sensitive technology we are identifying the amounts, kinds, and sources of spontaneous DNA damage in single living cells. Spontaneous DNA damage is thought to be the main culprit underlying genetic and genomic instability in all living cells. We discovered that spontaneous DNA double-strand breaks are rarer and more dangerous to genomes than predicted and that bacteria with DNA damage undergo a senescence-like state, analogous to that in human cells.
FROM BACTERIA TO HUMAN: GENOMIC CARETAKER PROTEINS AND CANCER. Genomic instability including mutagenesis and chromosome rearrangement is a hallmark of cancer, yet the genomic caretaker proteins that prevent and sometimes cause instability are highly conserved and similar in all organisms. E. coli RecQ is a close relative of five human proteins, mutations in at least three of which cause genome instability underlying cancer-predisposition syndromes: Bloom, Werner, and Rothmund-Thomson. One of the human, the yeast and fly RecQ homologues, appear to play one specific role in genetic recombination in cells. Surprisingly, we found that E. coli RecQ plays the opposite role, and thus exemplifies a second paradigm for the in vivo function of RecQ-family proteins. We are investigating whether any of the human homologues function via the E. coli RecQ paradigm, and the molecular basis of RecQ action in vivo as a model for human oncogenesis. We are pursuing other promising bacterial homologues of human cancer proteins to learn their mechanisms of action first in the simpler, more tractable bacterial system to provide mechanisms and models for the molecular bases of cancer.
Selected Publications
- Zhai Y, Pribis JP, Dooling SW, Garcia-Villada L, Minnick PJ, Xia J, Liu J, Mei Q, Fitzgerald D, Herman C, Hastings PJ, Costa-Mattioli M, Rosenberg SM "Drugging evolution of antibiotic resistance at a regulatory network hub." Sci Adv. 2023 Jun 23;9(25):eadg0188. Pubmed PMID: 37352342
- Zhai Y*, Minnick PJ*, Pribis JP, Garcia-Villada L, Hastings PJ, Herman C†, and Rosenberg SM† "ppGpp and RNA-polymerase backtracking guide antibiotic-induced mutable gambler cells." Mol Cell. 2023;83:1298-1310. Pubmed PMID: 36965481
- Mei Q*, Fitzgerald DM*, Liu J, Xia J, Pribis JP, Zhai Y, Nehring RB, Paiano J, Li H, Nussenzweig A, Hastings PJ, Rosenberg SM "Two mechanisms of chromosome fragility at replication-termination sites in bacteria." Sci Adv.. 2021 Jun 18;7(25):eabe2846. Pubmed PMID: 34144978
- Xia J*, Chiu L-Y*, Nehring RB, Bravo Núñez MA, Mei Q, Perez M, Zhai Y, Fitzgerald DM, Pribis JP, Wang Y, Hu CW, Powell RT, LaBonte SA, Jalali A, Lentzsch AM, Matadamas Guzman ML, Lentzsch AM, Szafran AT, Joshi M, Herman C†, Miller KM†, Rosenberg SM† "Bacteria-to-human protein networks reveal origins of endogenous DNA damage.." Cell. 2019 10;176:127-143. Pubmed PMID: 30633903
- Pribis JP, Garcia-Villada L, Zhai Y, Lewis-Epstein O, Wang A, Liu J, Xia J, Mei Q, Fitzgerald DM, Bos J, Austin RH, Herman C, Bates D, Hadany L, Hastings PJ, and Rosenberg SM. "Gamblers: an antibiotic-induced evolvable cell subpopulation differentiated by reactive-oxygen-induced general stress response.." Molecular Cell. 2019;74:785-800. Pubmed PMID: 30948267
- Sivaramakrishnan P, Sepulveda LA, Halliday JA, Bravo Núñez MA, Liu J, Golding I, Rosenberg SM, and Herman C "The transcription fidelity factor GreA impedes DNA break repair in Escherichia coli." Nature. 2017;550:214-218. Pubmed PMID: 28976965
- Xia J*, Chen L-T*, Mei Q*, Ma C-H, Halliday JA, Lin H-Y, Magnan D, Pribis JP, Fitzgerald DM, Hamilton HM, Richters M, Nehring R, Shen X, Li L, Bates D, Hastings PJ, Herman C, Jayaram M, and Rosenberg SM "Holliday junction trap shows how cells use recombination and a junction-guardian role of RecQ helicase." Science Advances. 2016;AAAS 2(e1601605) Pubmed PMID: 28090586
- Rosenberg SM, Queitsch C "Combating evolution to fight disease." Science. 2014 Mar 7;343(6175):1088-9. Pubmed PMID: 24604189
- Shee C, Cox BD, Gu F, Luengas EM, Joshi MC, Chiu LY, Magnan D, Halliday JA, Frisch RL, Gibson JL, Nehring RB, Do HG, Hernandez M, Li L, Herman C, Hastings P, Bates D, Harris RS, Miller KM, Rosenberg SM "Engineered proteins detect spontaneous DNA breakage in human and bacterial cells." Elife. 2013 Oct 29;2:e01222. Pubmed PMID: 24171103
- Al Mamun AA, Lombardo MJ, Shee C, Lisewski AM, Gonzalez C, Lin D, Nehring RB, Saint-Ruf C, Gibson JL, Frisch RL, Lichtarge O, Hastings PJ, Rosenberg SM "Identity and function of a large gene network underlying mutagenic repair of DNA breaks." Science. 2012 Dec 7;338(6112):1344-1348. Pubmed PMID: 23224554
- Wimberly H, Shee C, Thornton PC, Sivaramakrishnan P, Rosenberg SM, Hastings PJ "R-loops and nicks initiate DNA breakage and genome instability in non-growing Escherichia coli." Nat Commun. 2013;4:2115. Pubmed PMID: 23828459
- Shee C, Gibson JL, Rosenberg SM "Two Mechanisms Produce Mutation Hotspots at DNA Breaks in Escherichia coli." Cell Rep. 2012 Oct 25;2(4):714-21. Pubmed PMID: 23041320
- Shee C, Gibson JL, Darrow MC, Gonzalez C, Rosenberg SM "Impact of a stress-inducible switch to mutagenic repair of DNA breaks on mutation in Escherichia coli." Proc Natl Acad Sci USA. 2011 Aug 16;108(33):13659-64. Pubmed PMID: 21808005
- Pennington JM, Rosenberg SM "Spontaneous DNA breakage in single living Escherichia coli cells." Nat Genet. 2007 Jun;39(6):797-802. Pubmed PMID: 17529976
- Ponder RG, Fonville NC, Rosenberg SM "A switch from high-fidelity to error-prone DNA double-strand break repair underlies stress-induced mutation." Mol Cell. 2005 Sep 16;19(6):791-804. Pubmed PMID: 16168374
- Hastings PJ, Bull HJ, Klump JR, Rosenberg SM "Adaptive amplification: an inducible chromosomal instability mechanism." Cell. 2000 Nov 22;103(5):723-31. Pubmed PMID: 11114329
- Rosenberg SM, Longerich S, Gee P, Harris RS "Adaptive mutation by deletions in small mononucleotide repeats." Science. 1994 Jul 15;265(5170):405-7. Pubmed PMID: 8023163
- Harris RS, Longerich S, Rosenberg SM "Recombination in adaptive mutation." Science. 1994 Apr 8;264(5156):258-60. Pubmed PMID: 8146657
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