Overview

Our research focuses on chemical carcinogenesis with emphasis on the structural and conformational aspects of DNA-adduct formation. We are interested in how environmental carcinogens, upon metabolism, interact with cellular DNA to initiate mutagenesis/carcinogenesis.  The long-range goal of our research is to elucidate the mechanisms of mutation and repair at the atomic and molecular-genetic level.   In addition, we recently turned our attention to the emerging contaminants per- and polyfluoroalkyl substances (PFASs) and their interactions with certain essential proteins.

• RI-INBRE secures $21 million NIH grant to support biomedical research and training across Rhode Island - Latest round of funding increases URI-based program’s investment in biomedical research to more than $100 million since 2001
• “R.I. DLT renews funding for university biotech program” – Providence Business News, May 14, 2024
• “Pilot program trains biomedical students” – Providence Business News, June 21-July 4, 2024
• Providence Journal Op-Ed: Alliance transforming RI’s biomedical research landscape - Federal research grants are vital to building and maintaining world-class research programs. The University of Rhode Island recently secured a five- year, $21-million grant from the National Institutes of Health to support the Rhode Island IDeA Network of Biomedical Research Excellence program. Since its inception in 2001, the program has brought more than $100 million to the state.
• URI awarded $20 million to further expand biomedical research capacity in R.I. - A University of Rhode Island-based initiative that has successfully expanded biomedical research capacity at nearly all of Rhode Island’s universities and colleges has been awarded another $20 million in federal funding to further expand the program over the next five years.
• Providence Journal- R.I. businesses can tap into URI’s Business Engagement Center for help - PROVIDENCE — When The Pizza Gourmet, a Warwick-based maker of wood-grilled pizza crusts, started planning how to keep up with growing sales, co-owner Jack Parente called the University of Rhode Island for some help.Parente, a URI graduate, wanted to know if anyone at the university could design a more efficient grill to cook the crusts […]
• URI’s YouTube Site - 3D biomedical science videos receives 1 million hits KINGSTON, R.I. – Dec. 10, 2012 – It can be difficult to understand how drugs like Iressa and Prozac work in the body just from reading a textbook. That’s why students at the University of Rhode Island have been creating 3D models and animations to explain complex […]
• Join the fight against cancer - Grilling season is in full swing, and the age-old question hangs in the air:  Would you like a side of carcinogenic heterocyclic amines with your porterhouse?  That black stuff you love so much on your grilled meat is nearly as bad as eating soot from your fireplace and can actually be hazardous to your health. […]
• URI researchers ask, ‘Is your health at steak?’ - URI researchers ask, ‘Is your health at steak?’ KINGSTON, R.I. – Nothing goes better with your Fourth of July fireworks than a backyard barbecue. But if you’re not careful, your grilled meats could be a health hazard. According to two URI scientists, the charring on your steaks and burgers are heterocyclic amines or, if you’ve […]
• Discovering the Configuration of Cancer - Dr Bongsup Cho offers an insight into his current research into environmentally-induced cancer, which will expose how aromatic amines mutate DNA and interfere with its repair mechanisms. Could you briefly describe your current research project? Formation of aromatic amine-DNA adducts is believed to initiate cancer. We are concerned with elucidating the mechanisms by which amine-DNA […]

Research

• Arylamine DNA adduct recognition in eukaryotic nucleotide excision repair (NIH/NIEHS 5R21 ES028384) in collaboration with Dr. Jung Hyun Min at Baylor University

  Aromatic amines are among the most notorious environmental chemicals. At pathologically relevant concentrations, their reactive metabolites can react with cellular DNA to produce bulky lesions. If not efficiently repaired, these lesions can result in mutations that lead to various sporadic cancers. Understanding the mechanisms by which these lesions are recognized by the XPC nucleotide excision repair complex is the focus of this proposal.
  

  

  

  Project Summary

  The human genome is under constant assault by environmental factors that include sunlight and chemicals. Arylamines are diverse and ubiquitous environmental mutagens implicated in the etiology of various sporadic cancers. Direct exposure to arylamines, such as 4-aminobiphenyl (ABP), increases the risk of bladder cancer, the fourth most common cancer in men in the US. Arylamines absorbed into the cells are activated and react with cellular DNA to produce bulky DNA adducts. If not efficiently repaired, these lesions can result in mutations and tumorigenesis. Nucleotide excision repair (NER) is a key repair pathway that protects the integrity of the genome against diverse DNA lesions including arylamine adducts. To initiate NER, the xeroderma pigmentosum C (XPC) protein complex first detects the lesions and recruits downstream factors, which in turn verify, excise and restore the damaged portion of the DNA. Though it has been generally believed that stable, specific binding to XPC is required for efficient repair, we recently found that it is not always true: for certain arylamine lesions in a highly mutagenic sequence context, an extremely tight binding to XPC (due to a slow dissociation rate) may, in fact, hamper NER (Hilton et al., PLos One e0157784 (2016)). In this project we will collaborate with Dr. Junghyun Min at Baylor University to investigate the structural and mechanistic basis underlying this intriguing relationship between the XPC-binding and repair potentials of arylamine lesions. We will use a powerful multidisciplinary approach that combines the complementary strengths of ¹⁹F-NMR, surface plasmon resonance (SPR), and X-ray crystallography. The knowledge gained on how certain lesions evade repair while tightly binding to repair proteins, may also lead to novel ideas and agents to combat cancer.

• Mutational spectra of bulky DNA lesions (NIEHS 5R01ES028865) in collaboration with Dr. Deyu Li (PI) at The University of Rhode Island

  Many aromatic amines are environmental toxins and human carcinogens. They damage genome and form different bulky DNA lesions, which give rise to different mutation patterns. This application will study the mutational spectra of bulky DNA lesions generated from aromatic amine exposure and provide insights into the development of tumors.

  

  Project Summary

  Many environmental toxins damage DNA and cause diseases. The exposure of cells with DNA damaging agents results in the formation of a host of different DNA lesions, a subset of which can give rise to mutations. If one were to plot the frequency and type of mutation as a function of the position along a gene, a distribution is generated that is commonly referred to as a mutational spectrum. It is reasonable to speculate that mutational hotspots are modulated by the local sequence environment surrounding the base to be modified, or the DNA lesion to be repaired or replicated. It is important for environmental scientists to provide insights into the evolutionary changes that foreshadow tumor development before overt clinical symptoms appear. This goal is crucial because some diseases, such as tumors, show few clinical symptoms until the disease has reached a late, usually fatal stage. Early onset genomic biomarkers might enable intervention to eliminate or curtail development of the disease. The biomarkers of a disease caused by a specific toxin can be obtained by studying the mutational spectra of DNA lesions generated from the toxin. Experimental studies of the mutations and mutation spectra induced by environmental toxins have traditionally focused on single mutations. However, the origins of mutational hotspots is complicated by the neighboring contexts. The selective formation, replication, and repair of a DNA lesion can, in principle, be influenced by the surrounding nucleotide environment from both 5’ and 3’ ends. A nearest-neighbor analysis of a certain DNA lesion (NXN, X = lesion, N = one of the four nucleotides) will provide a structural rationale for mutational spectra in environmental toxin related human tumors. In this proposal, we will study individual lesions of environmental toxins under all the genetic and epigenetic relevant contexts. In this project, we select two important environmental toxins, 4-amino biphenyl (ABP) and amino alpha carboline (AaC) to study the mutational spectra of their major DNA lesions and correlate with mutational signatures of diseases caused by them. The central hypothesis of this project is that DNA lesions generated by environmental toxins will cause different mutational spectra in a sequence dependent manner. The Specific Aims are: Specific Aim 1: Chemical synthesis and identification of bulky DNA adduct containing oligonucleotides. Specific Aim 2: Mutational spectra of bulky lesions in cell. Specific Aim 3: Replication bypass of lesions by translesion synthesis polymerases. At the conclusion of this project we will have demonstrated how the interaction between environmental toxins and mutational spectra. These studies shall utilize in a combination of genetic, chemical, and spectroscopic tools to understand and manipulate biological systems at the molecular level.

• Protein binding of per- and polyfluoroalkyl substances (PFASs) as part of URI/Harvard Superfund STEEP (NIH/NIEHS 3P42ES027706)

  

  

  
  Per- and polyfluoroalkyl substances (PFASs) are used to make surfaces water and oil resistant and can be found in cookware and fabric, as well as firefighting foam. They are ubiquitous and are contaminating water supplies near manufacturing plants and fire training sites.  PFASs are present in blood serum of 99% of human population worldwide. To make matters worse, there are almost 5,000 PFASs in the environment. US EPA has recently declared PFASs as a national priority. PFASs have been found epidemiologically to cause cancer and cardiovascular risk, thyroid disease, and immune system disorders, but their mode of actions is not understood.  We hypothesize that PFASs may occupy important pockets of certain essential enzymes and receptors disrupting their regular functions. These chemicals can have long lasting adverse effects because of their unusually long half lives (years). To this end, we will use a powerful combination of microcalorimetry (ITC and DSC) and real time binding measurements such as surface plasmon resonance (SPR) to study systematically their specific interactions with human serum albumin protein (HAS) and transthyretin.  We will collaborate with the project leaders involved in the URI/Harvard joint STEEP Superfund Research Program (SRP) (https://web.uri.edu/steep/). Dr. Cho is Training Core leader of the URI/Harvard STEEP Collaboration.

Publications

Complete List of Peer-Reviewed Publications (*corresponding authorship)

Research Team

From Left to Right:

• Bongsup Cho
• Ang Cai
• Rachel Carley
• Alicia Crisalli
• Allen Schroeder
• Mimi Ji

Bongsup Cho, Ph.D.

• Professor
• Phone: 401.874.5024
• Email: bcho@uri.edu