F. Bradley Johnson, MD, PhD

Description of Research Expertise

Research Interests
Molecular biology of aging, Werner syndrome, telomeres,
recombination, G-quadruplexes.

Key words: Aging, telomeres, recombination, Werner syndrome, cancer, yeast, mice, G-quadruplex.

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 (in collaboration with Drs. Shelley Berger [Penn], Ronen Marmorstein [Wistar Institute] and Peter Adams [Beatson Institute]). 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, DNA recombination and transcription in vivo. Most of our studies are being pursued in yeast, because they provide an ideal system in which to study the functions of these fascinating structures. Bioinformatics and structural approaches to understanding G-quadruplex function are also being carried out in collaboration with the laboratories of Dr. Li-San Wang (Penn) and Liliya Yatsunyk (Swarthmore College).

A third focus of the lab is to use the mouse model lacking telomerase and the Werner gene that we generated and characterized several years ago 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, including gastrointestinal pathology in collaboration with Drs. John Lynch and Anil Rustgi (Department of Medicine). We are also pursuing collaborative work with the laboratory of Dr. Robert Pignolo (Department of Medicine) to better understand how osteoblast senescence and dysfunction contributes to osteoporosis in these mice.

A fourth interest of the lab is the measurement in clinical specimens of telomere lengths and capping, and telomerase activity. These translational projects are being carried out in collaboration with Deborah Cohen (Department of Medicine) and Harold Riethman (Wistar Institute).

Rotation Projects
Please contact Dr. Johnson to discuss potential rotation projects.

Lab Personnel
Qijun Chen, PhD, Research Specialist
Jay Johnson, PhD, Postdoc
Jen Wanat, PhD, Postdoc
Jesse Platt, MD-PhD student
Ting Yang, MD-PhD student
Becky Billmire, PhD student
Jordan Driskill, Undergraduate
Sybil Ozcelik , Undergraduate
Arjuna Keshavan, Undergraduate
Rebecca Duncan, School of Nursing
Sarah Hsu, MD-PhD rotation student

Description of Clinical Expertise

HLA and transplantation testing