Defects in the Regulation of Genome Duplication can Lead to Cancer

Novel models for cancer diagnosis, therapy, and prevention

Cancer is a disease of runaway cell division. Duplication of DNA, the hereditary material, must occur before cell division ensues. Therefore, understanding what regulates the initiation of DNA synthesis will uncover the checkpoint that regulates the onset of cell division. DNA carries the blueprint of life. It is crucial that it be duplicated perfectly to pass exact copies to the daughter cells. Dr. Susan Gerbi, the George Eggleston Professor at Brown University, seeks to understand origins of DNA replication where DNA synthesis begins. Identification of the many replication origins in the genome will elucidate the molecular mechanisms regulating the initiation of DNA synthesis and the coordination of cell growth and cell division. Dr. Gerbi and her team are working to translate their findings into new modes of cancer diagnosis, therapy, and prevention. Her studies to get at the heart of the matter by understanding molecular mechanisms fuel her passion to translate these basic findings into improvement of human health.

Dr. Gerbi uses many models, ranging from yeast, flies, frogs, and cultured human cells, selecting the organism whose biology is best suited to address the question at hand to elucidate fundamental mechanisms. Blending postdoctoral research associates, graduate students, a research assistant, and talented undergraduates engaged in their senior honor’s thesis research projects, Dr. Gerbi’s lab is promoting future generations of biologists with rigorous and meaningful work using cutting edge methods of molecular and cell biology and genomics. While different projects within the lab are advancing towards novel insight each day, of exceptional importance to Dr. Gerbi is the translation of her basic experiments into clinical applications. For instance, her current experiments may translate into ways to combat cancer as well as provide new antibiotics to combat infection.

Current research topics include:

  •  What defines where DNA synthesis will start? To address this question, Dr. Gerbi is developing new methods to map regions of DNA replication in the genome. Using yeast cells, Dr. Gerbi’s lab developed the method of Replication Initiation Point (RIP) mapping to allow the start site of DNA synthesis to be mapped with nucleotide resolution; since then RIP mapping has been applied to multicellular organisms. Dr. Gerbi’s team is now developing new methods for genomic analysis of DNA replication origins, using yeast as a control where all its replication origins are known. Their new methodology will then be used to map replication origins in the human genome.
  • How do rogue origins bypass the cellular controls that normally allow origin activation only once per cell cycle? When certain origins are activated repeatedly in the same cell cycle, this leads to gene amplification, a hallmark of cancer where there are extra copies of oncogenes. It is difficult to study the initiating events of DNA amplification in cancer cells since the trigger is unknown. Dr. Gerbi is making use of the fly Sciara where site-specific DNA amplification at DNA puffs in giant chromosomes is part of its normal development. Results of RIP mapping identified the nucleotide where re-replication begins in a DNA puff, and inspection of the DNA sequence revealed a binding site for a hormone receptor adjacent to the re-replication origin. With their completion of determination of the sequence of the Sciara genome and development of technology for genome engineering in Sciara, the Gerbi lab is now poised to test the hypothesis that the steroid-bound hormone receptor is the trigger for DNA puff amplification.
  • Can the molecular mechanism for gene amplification in flies serve as a paradigm for gene amplification in cancer? To address this question, the results from the fly model are informing the design of experiments in the Gerbi lab using cultured human cancer cells. They are asking if steroid hormones are the long sought after trigger for gene amplification, especially in hormonally sensitive cancers such as breast cancer and prostate cancer. For example, HER2 gene amplification occurs in ~25% of invasive breast cancers and in 50% of ductal carcinoma in situ and promotes growth of cancer cells in a variety of tissue environments, acting as a metastasis-promoting factor. Moreover, cancer cells with HER2 amplification commonly show resistance to the anti-estrogen reagent tamoxifen, resulting in endocrine therapy unresponsiveness. Elucidation of the initiating events and mechanism of gene amplification in cancer could lead to new approaches for cancer diagnosis and therapy, with the long-term goal to enable cancer prevention.
  • What coordinates cell growth with cell division? How does a cell know when it has gotten big enough and it is time to divide? In order to grow, cells use ribosomes that are the cellular factories that produce proteins. Early on, Dr. Gerbi’s lab sequenced the first ribosomal RNA (rRNA) in multicellular organisms (frogs), and since then have been leaders in understanding its structure, biogenesis and evolution. Their recent research shows that the cell cycle halts and DNA synthesis does not start when ribosome biogenesis is arrested. Elucidation of the molecular mechanism underlying this could provide novel means for cancer therapy.
  • What are new targets for new antibiotics? Bioinformatic studies from the Gerbi lab have identified conserved nucleotide elements in rRNA as targets for a new class of antibiotics to combat bacterial infection. Ribosomes are the target of more than half of all antibiotics, as interfering with ribosome function blocks protein synthesis and thus arrests growth of the bacterial pathogen. Modern medicine has an impending crisis with the dramatic increase in antibiotic resistance. This problem is also important for the health and safety of citizens of our nation, as germ warfare could introduce pathogenic bacteria with antibiotic resistance. Dr. Gerbi’s experiments have uncovered two regions in rRNA that are conserved in all forms of bacteria but not conserved in eukaryotes. These can serve as novel targets for new antibiotics using approaches from RNA therapeutics.

Visit her website at https://www.brown.edu/research/labs/gerbi/

Bio

Growing up, Dr. Gerbi’s father, Claudio Gerbi, was her role model. As a faculty member at Columbia University College of Physicians and Surgeons, he had a private practice in internal medicine, and carried out research on renal hypertension. Through her father, Dr. Susan Gerbi gained an appreciation of how research in fundamental biological mechanisms can have great significance and translation in medical applications. As a high school student, she accompanied her father at research seminars held at the New York Academy of Sciences and heard talks by eminent scholars. One of these talks was by George Palade, who went on to win the Nobel Prize for his work on ribosomes (the cellular factories for protein synthesis). This kindled her interest and future research on ribosomes. 

Also while enrolled in a stimulating Advanced Placement Biology course in high school, Dr. Gerbi wrote a term paper on chromosome structure and DNA replication, using review articles by J. Herbert Taylor as the factual base. Two years later, as a Sophomore at Barnard College, she had the great pleasure of taking a Molecular Genetics course at Columbia University from the very same Professor Taylor. This clinched her deep interest in understanding the mechanism of DNA replication as well as a broader interest in chromosome structure. 

Her fascination with ribosomes and chromosomes coalesced in her predoctoral graduate research with Professor Joe Gall, at Yale University, where she was a member of his team that developed the technique of in situ hybridization, allowing DNA sequences to be mapped on chromosomes. For these experiments Dr. Gerbi and the rest of the team mapped the genes for ribosomal RNA on the chromosome. The method of in situ hybridization set the stage and helped to usher in the modern era of genomics.

Professor Joe Gall’s stellar career has time and time again demonstrated the value of choosing the best, and often unique, biological system to study the specific research question at hand. Following this dictum, Dr. Gerbi has used yeast, flies, frogs and cultured human cancer cells for her research.

In her free time, Dr. Gerbi enjoys the creativity of gardening and landscape design. Additionally, as an amateur architect, Dr. Gerbi has designed and built an energy efficient Georgian colonial home. She also enjoys horseback riding and has competed in dressage and jumping.

Website: http://www.brown.edu/go/gerbilab

Awards

Fellow of AAAS, 2008-current

Recipient of Rhode Island Governor’s Award for Scientific Achievement, 1993

American Society for Cell Biology

President, 1993; Chair of Women in Cell Biology, 1991; Council, 1988-1990; Program Chair, 1986

Patents

Methods to screen for antibiotic agents and their use in treatment of opportunistic infections.

U.S. Patent No. PCT/OS01/20520. Inventors: Gerbi SA, Lange TS and Borovjagin AV. Issued 2000.

Conserved nucleotide elements in ribosomal RNA.

U.S. Patent No. 14/204,223. Inventors: Gerbi, SA, Doris SM, Smith DR, Beamesderfer JN and Raphael B. Issued 2014. U.S. Patent Application.