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Harold C. Smith, Ph.D.

Contact Information

University of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, Box 712
Rochester, NY 14642

Office: (585) 275-4267
Fax: (585) 275-6007
Lab: (585) 275-1882

Research Bio

Normal and cancer cells express more diversity in proteins than can be accounted for by the predicted number of expressed genomic DNA sequence. Expansion of the genomically encoded expressed sequences through alternative processing of RNA, such as mRNA editing, is a logical hypothesis for how protein diversity and variations seen as tissue-specific and regulated expression of proteins can be achieved. The specific focus of the research is to identify and characterize novel mammalian mRNA editing systems that employ a zinc-dependent deamination mechanism for the post-transcriptional conversion of cytidine to uridine at select sites within mRNAs. Computational modeling has suggested a family of mammalian enzymes known as Cytidine Deaminases Active on RNA or CDARs as responsible for C to U editing of mRNAs.



The expression of these enzymes in biology suggests that mRNA editing may be involved in numerous physiological processes and could be manipulated for the prevention of cardiovascular disease, HIV infection and cancer, and is also necessary for production of antibodies in B lymphocytes. Recent evidence indicates that the enzyme involved in suppressing HIV-1 infectivity (CEM15) and the enzyme that promotes antibody production (AID) may act to mutate deoxy cytidine in DNA rather than or in addition to RNA.

Our research involves molecular biology and protein techniques, DNA microarray analyses and computational biology to identify the mRNAs that are edited by CDARs and to determine the biological consequence of these editing events in terms of the predicted changes in the types of protein structures and functions that can be expressed. Our studies have demonstrated how cytidine to uridine mRNA editing contributes to expansion in the diversity of expressed mRNA sequences known collectively as the transcriptome.

We are also evaluating the regulatory mechanisms controlling the expression of editing factors and their localization in the cell nucleus. The development of this new information will establish an important new annotation of the human genome that will serve as a frame of reference for studies of proteins involved in health and disease and mechanisms regulating their expression.

Recent Journal Articles

Showing the 5 most recent journal articles. 96 available »

2016 Sep 1
Polevoda B, McDougall WM, Bennett RP, Salter JD, Smith HC. "Structural and functional assessment of APOBEC3G macromolecular complexes." Methods : a companion to Methods in enzymology. 2016 Sep 1; 107:10-22. Epub 2016 Mar 14.
2016 Jan 15
Hilimire TA, Bennett RP, Stewart RA, Garcia-Miranda P, Blume A, Becker J, Sherer N, Helms ED, Butcher SE, Smith HC, Miller BL. "N-Methylation as a Strategy for Enhancing the Affinity and Selectivity of RNA-binding Peptides: Application to the HIV-1 Frameshift-Stimulating RNA." ACS chemical biology. 2016 Jan 15; 11(1):88-94. Epub 2015 Nov 03.
2015 Oct 30
Polevoda B, McDougall WM, Tun BN, Cheung M, Salter JD, Friedman AE, Smith HC. "RNA binding to APOBEC3G induces the disassembly of functional deaminase complexes by displacing single-stranded DNA substrates." Nucleic acids research. 2015 Oct 30; 43(19):9434-45. Epub 2015 Sep 30.
2014 Sep
Salter JD, Morales GA, Smith HC. "Structural insights for HIV-1 therapeutic strategies targeting Vif." Trends in biochemical sciences. 2014 Sep; 39(9):373-80. Epub 2014 Aug 12.
2014 Feb 13
Ofori LO, Hilimire TA, Bennett RP, Brown NW, Smith HC, Miller BL. "High-affinity recognition of HIV-1 frameshift-stimulating RNA alters frameshifting in vitro and interferes with HIV-1 infectivity." Journal of medicinal chemistry. 2014 Feb 13; 57(3):723-32. Epub 2014 Jan 15.

Current Appointments

Professor - Department of Biochemistry and Biophysics (SMD) - Primary

Education

PhD | Molecular Biology | St Univ at Buffalo1982
MA | Molecular Biology | St Univ at Buffalo1980
MS | Veterinary Medicine | Purdue University1978
BS | Biology | Purdue University1975