F. Bradley Johnson, MD, PhD
Associate Professor of Pathology and Laboratory Medicine
University of Pennsylvania Perelman School of Medicine
Contact InformationDepartment of Pathology and Laboratory Medicine
Stellar Chance, 405A
422 Curie Blvd.
University of Pennsylvania
Philadelphia, PA 19104-6100
Laboratory Medicine, Immunobiology and Experimental Pathology
Molecular biology of aging, cell senescence, Werner syndrome, telomeres,
recombination, G-quadruplexes, neurodegeneration, transplantation.
Key words: Aging, telomeres, recombination, Werner syndrome, cancer, yeast, mice, G-quadruplex, neurodegeneration, transplantation.
Description of Research
Our lab is interested in the biology of human aging and cancer, and we are focusing particularly on how they are influenced by telomere maintenance and dysfunction. Telomeres are the structures that cap the ends of chromosomes, and this location makes them critical for genome stability as well as particularly susceptible themselves to a variety of insults including oxidative damage, exonucleolytic attack, and inappropriate processing by recombination factors.
One focus of the lab is to investigate mechanisms of telomere maintenance. We have identified roles for the RecQ family DNA helicases in coordinating recombination-dependent mechanisms that maintain telomeres. This family of helicases includes those that are deficient in the Werner and Bloom syndromes, which are diseases characterized by premature aging and elevated rates of cancer. Our findings in mice and yeast have helped establish telomere defects as an important cause of the clinical phenotypes observed in these syndromes. More recently, we have also begun exploring roles for chromatin regulatory factors, including SUMO modifiers and regulators of histone acetylation, in telomere maintenance. We hope that by better understanding how RecQ helicases and chromatin factors maintain telomeres, new methods for preserving telomere function in normal tissues and for disrupting telomere function in malignancies may be developed.
A second focus of the lab is to investigate the biology of G-quadruplexes, which are four-stranded DNA structures formed by G-rich sequences like telomeres. The RecQ family of helicases, including WRN and BLM, are particularly adept at unwinding G-quadruplexes. Recently, we have obtained evidence that G-quadruplexes regulate telomere capping, cell senescence, DNA recombination and transcription in vivo. Cell biologic, bioinformatic and structural approaches to understanding G-quadruplex function are being pursued.
A third focus of the lab is to use a mouse model lacking telomerase to learn more about the mechanisms by which telomere dysfunction contributes to age-related pathology. We are investigating how transplantation of normal bone marrow and manipulation of the Wnt pathway rescues this and other degenerative phenotypes in these mice.
A fourth interest of the lab is the measurement in human clinical specimens of telomere lengths and capping, telomerase activity, chromatin regulators, and cell senescence. We are particularly interested in understanding how these factors contribute to age-related neurodegenerative diseases and the success of transplanted tissues.
Please contact Dr. Johnson to discuss potential rotation projects.
Qijun Chen, PhD, Research Specialist
Jay Johnson, PhD, Research Associate
Jen Wanat, PhD, Postdoc
Jesse Platt, MD-PhD student
Ting Yang, MD-PhD student
Becky Billmire, PhD student
Jordan Driskill, Undergraduate
Rebecca Duncan, School of Nursing
Shufei Song, PhD student
HLA and transplantation testing
Dr. Johnson is primarily interested in mechanisms of telomere maintenance and genome stability, and how these relate to age-related pathology, including cancer and neurodegenerative diseases. His lab studies roles for DNA helicases (Werner and Bloom syndrome helicases) and chromatin and metabolic regulators in these processes. Experimental approaches are taken in model organisms (yeast, mice, culture cells) as well as clinical samples (human brain, pancreas, and kidney).
Biochemistry and Molecular Biophysics
Cell and Molecular Biology
B.S. (Molecular Biophysics & Biochemistry), Yale University , 1987
M.D. Stanford University School of Medicine, 1995
Ph.D. (Biochemistry), Stanford University School of Medicine , 1995
Postdoc (Aging Biology), Massachusetts Institute of Technology, 2001
Residency (Clinical Pathology), Brigham and Women's Hospital, 2001
American Board of Pathology in Clinical Pathology, 2000
Resident in Clinical Pathology, Brigham and Women’s Hospital, Boston, 1995-1999
Postdoctoral Research in Biology, Massachusetts Institute of Technology, Cambridge, 1997-2001
Research Fellow in Pathology, Brigham and Women’s Hospital, Boston, 1999-2001
Awards and Honors
National Merit Scholar, Yale University, 1983-1987
Summer Undergraduate Research Program Fellowship, Cold Spring Harbor Laboratories, 1986
Elected to the Sigma Xi scientific society, 1987
Award for outstanding technical contribution, Institute of Environmental Sciences, 1987
Magna cum laude and distinction in the major, Yale University, 1987
Medical Scientist Training Program,
Stanford University School of Medicine, 1987-1995
Mentored Clinical Scientist Development Award (K-08), 1997-2001
Chief Resident, Clinical Pathology, Brigham and Women’s Hospital, 1997
Howard Hughes Medical Institute
Postdoctoral Fellowship for Physicians, 1998-1999
Paul E. Strandjord Young Investigator Award, 1998
Paul E. Strandjord Young Investigator Award, with distinction, 2000
Paul Beeson Scholar in Aging Research Award, 2002-present
Peter C. Nowell Teaching Award, 2006
Dorothy Dillon Eweson Lecturer on Advances in Aging Research / American Federation for Aging Research, 2009
Dorothy Dillon Eweson Lecturer on Advances in Aging Research / American Federation for Aging Research, 2012
Dorothy Dillon Eweson Lecturer on Advances in Aging Research / American Federation for Aging Research, 2015
Memberships and Professional Organizations
NIH P01 on DNA Repair, Mutations and Cellular Aging, 2003 - Present
NIH Genetic And Molecular Basis of Longevity RFA, 2004 - 2004
NIH Cellular Mechanisms of Aging and Development (CMAD) Study Section, 2004 - 2012
Kentucky Science and Engineering Foundation, 2005 - Present
American Federation for Aging Research, 2005 - Present
National Institute on Aging Advisory Committee for the Animal Models of Comorbidity in Aging Advisory Workshops, 2006 - 2007
A*STAR Biomedical Research Council of Singapore, 2007 - 2008
University of Michigan Geriatrics Center Pilot Grant Program, 2007 - Present
W.M. Keck Foundation, 2007 - 2007
NIH Special Emphasis Panel/Scientific Review Group 2008/10 ZRG1 BDA-A (02), 2008 - Present
NIH Molecular Genetics C Study Section, 2008 - Present
NIH Special Emphasis Panel/Scientific Review Group 2009/10 ZAG1 ZIJ-2 (O5), 2009 - Present
Nathan Shock Center of Excellence in The Basic Biology of Aging,
University of Washington, 2009 - 2009
Ellison Foundation/American Federation for Aging Research, 2013 - 2013
NIH Cellular Mechanisms of Aging and Development (CMAD) Study Section., 2013 - Present
Evaluation Committee of the French National Research Agency (ANR), 2015 - Present
Czech Academy of Sciences (ASCR), 2015 - Present
European Research Council, 2015 - Present
NIH Cellular Mechanisms of Aging and Development study section, 2016 - Present
Rap1 relocalization contributes to the chromatin-mediated gene expression profile and pace of cell senescence.
Jesse M. Platt, Paul Ryvkin, Jennifer J. Wanat, Greg Donahue, M. Dan Ricketts, Steven P. Barrett, Hannah J. Waters, Shufei Song, Alejandro Chavez, Khaled Omar Abdallah, Stephen R. Master, Li-San Wang, F. Brad Johnson, Genes and Development 27(12): 1406-20, 2013, PMID:23756653
Smith Jasmine S, Chen Qijun, Yatsunyk Liliya A, Nicoludis John M, Garcia Mark S, Kranaster Ramon, Balasubramanian Shankar, Monchaud David, Teulade-Fichou Marie-Paule, Abramowitz Lara, Schultz David C, Johnson F Brad, Nature Structural & Molecular Biology 18(4): 478-85, 2011, PMID:21399640
Homologous recombination-dependent rescue of deficiency in the structural maintenance of chromosomes (Smc) 5/6 complex.
Chavez Alejandro, Agrawal Vishesh, Johnson F Brad, The Journal of Biological Chemistry 286(7): 5119-25, 2011, PMID:21138837
Inactivation of the Sas2 histone acetyltransferase delays senescence driven by telomere dysfunction.
Kozak, ML, Chavez, A, Dang, W, Berger, SL, Ashok, A, Guo, X, and Johnson, FB., EMBO Journal 29(1): 158-70, 2010, PMID:19875981
J.N. Lukens, V. Van Deerlin, C.M. Clark, S.X. Xie, and F.B. Johnson, Alzheimer's and Dementia 5(6): 463-9, 2009, PMID:19896585
Altered gene expression in the Werner and Bloom syndromes is associated with sequences having G-quadruplex forming potential.
Johnson, JE, Cao, K, Ryvkin, P, Wang, L-S, and Johnson, FB, Nucleic Acids Research 38(4): 1114-1142, 2010, PMID:19966276
Sumoylation and the structural maintenance of chromosomes (Smc) 5/6 complex slow senescence through recombination intermediate resolution.
Chavez Alejandro, George Vanessa, Agrawal Vishesh, Johnson F Brad, The Journal of biological chemistry 285(16): 11922-30, 2010, PMID:20159973
Lee JY, Kozak M, Martin JD, Pennock E, Johnson FB., PLOS Biology 5(6): e160, 2007, PMID:17550308
Marciniak, R.A., Cavasos, D., Montellano, R., Chen, Q., Guarente, L., and Johnson, F.B., Cancer Res. 65(7): 2730-7, 2005, PMID:15805272
Du, X., Shen, J., Kugan, N., Furth, E.E., Lombard, D.B., Cheung, C., Pak, S., Luo, G., Pignolo, R.J., Guarente, L, and Johnson, F.B., Mol. Cell. Biol. 24(19): 8437-8446, 2004, PMID:15367665