Professor, Departments of Molecular and Human Genetics, Biochemistry & Molecular Biology, and Molecular Virology & Microbiology; Program in Cell & Molecular Biology; Dan L. Duncan Cancer Center

B.A., State University of New York, Potsdam, 1980
M.S., University of Oregon, 1981
Ph.D., University of Oregon, 1986
Postdoc, University of Paris VII, 1987
Postdoc, University of Utah, 1988
Postdoc, National Cancer Institute, Frederick Cancer Research and Development Center, 1990

RESEARCH INTERESTS:

Genome Instability in Evolution, Antibiotic Resistance, and Cancer

Stress-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 then. The mutation mechanism also includes temporary suspension of post-synthesis mismatch repair, resembling mutagenesis characteristic of some cancers. Stress-induced mutation mechanisms may provide important models for genome instability underlying some cancers and genetic diseases, resistance to chemotherapeutic and antibiotic drugs, 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 a mechanism with similarities to recombination-dependent stress-induced mutagenesis described above. We are examining the mechanism 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 Humans: 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-Thompson. 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:

1. Pennington JM, Rosenberg SM (2007). Spontaneous DNA breakage in single living Escherichia coli cells. Nat. Genet. 39: 797-802.

2. Magner DB, Blankschien MD, Lee JA, Pennington JM, Lupski JR, Rosenberg SM (2007). RecQ promotes toxic recombination in cells lacking recombination intermediate-removal proteins. Mol. Cell. 26: 273-286.

3. Ponder RG, Fonville NC, Rosenberg SM (2005). A switch from high-fidelity to error-prone DNA double-strand break repair underlies stress-induced mutation. Mol. Cell 19: 791-804.

4. Hastings PJ, Slack A, Petrosino JF, Rosenberg SM (2004). Adaptive amplification and point mutation are independent mechanisms: evidence for various stress-inducible mutation mechanisms. PLoS Biol. 2: e399.

5. Rosenberg SM, Hastings PJ (2004). Genomes: Worming into genetic instability. Nature 430: 625-626.

6. Rosenberg SM, Hastings PJ (2003). Modulating mutation rates in the wild. Science 300: 1382-1383.

7. Rosenberg SM (2001). Evolving responsively: Adaptive mutation. Nat. Rev. Genet. 2: 504-515.

8. Hastings PJ, Bull HJ, Klump JR, Rosenberg SM (2000). Adaptive amplification: An inducible chromosomal instability mechanism. Cell 103: 723-731.

9. Harris RS, Feng G, Thulin C, Longerich S, Ross K, Sidhu R, Szigety S, Winkler ME, Rosenberg SM (1997). Mismatch repair protein MutL becomes limiting during stationary-phase mutation. Genes Dev. 11: 2426-2437.

10. Torkelson J, Harris RS, Lombardo MJ, Nagendran J, Thulin C, Rosenberg SM (1997). Genome-wide hypermutation in a subpopulation of stationary-phase cells underlies recombination-dependent adaptive mutation. EMBO J. 16: 3303-3311.

11. Rosenberg SM, Longerich S, Gee P, Harris RS (1994). Adaptive mutation by deletions in small mononucleotide repeats. Science 265: 405-407.

For more publications, see listing on Pub Med.

AWARDS AND HONORS:

2006: 8-Stranded Beta-Barrel Jelly Roll Award for Best Course 2005 (Genetics A), Baylor College of Medicine Graduate Student Council
2002-present: The Cullen Foundation Endowed Professorship in Molecular Genetics, Baylor College of Medicine
2002: Endowed Lecture and Certificate, American Society for Microbiology Division X, (eukaryotes)
2001: Michael E. DeBakey Excellence in Research Award, Baylor College of Medicine
2001: 8-Stranded Beta-Barrel Jelly Roll Award for Best Course 2005 (Genetics A), Baylor College of Medicine Graduate Student Council
2000: 8-Stranded Beta-Barrel Jelly Roll Award for Best Course 2005 (Genetics A), Baylor College of Medicine Graduate Student Council
1997-2002: Medical Research Council of Canada, Scientist, salary award (declined 9/97-onward) 1997-2002 Alberta Heritage Foundation for Medical Research Senior Scholar, salary award (declined)
1996: The Young Scientist Award of the Genetics Society of Canada

CONTACT INFORMATION:

Susan M. Rosenberg, Ph.D.
Department of Molecular and Human Genetics
Baylor College of Medicine
One Baylor Plaza, Rm S809A
Houston, TX 77030, U.S.A.
Mail Stop: BCM225

Phone: 713-798-6924
Fax: 713-798-8967
E-mail:

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