Melissa Mefford

Degrees, Licensures and Certifications: BS, Biology, The College of William & Mary; PhD, Genetics, The University of Chicago

Research Interests: The evolution of telomeres and telomerase

BIO:

Telomeres, composed of repetitive DNA sequences at the termini of linear chromosomes, serve as protective caps. However, telomeres cannot be fully copied during replication without the ribonucleoprotein enzyme telomerase. Understanding the delicate balance between telomere length and telomerase activity has important implications for two of the biggest human health concerns: aging and cancer. Telomeres have been shown to shorten with age, acting as a “biological clock” limiting the rounds of division a cell can undergo. To circumvent this proliferative limit, over 85% of cancers aberrantly up-regulate telomerase expression. The long-term goals of the Mefford lab are to understand the evolution of telomeres and telomerase, and how these cellular components contribute to the health and lifespan of an organism.

To begin unraveling these broad fundamental questions, we will harness the awesome power of the simple eukaryotic model organism Saccharomyces cerevisiae, also known as baker's or brewer’s yeast, in two main projects. First, a screen for gain-of-function mutations in telomerase RNA will identify novel alleles that lengthen telomeres by increasing enzyme activity. Such gain-of-function mutants will shed new light on how the essential RNA component of telomerase contributes to the overall action of the enzyme. Second, yeast strains will be genetically engineered to circularize each of their 16 linear chromosomes, allowing novel experimental investigation of the advantages and disadvantages of circular chromosomes in a eukaryotic organism. These novel yeast strains will build a foundation for creating an innovative eukaryotic organism with all linear chromosomes circularized, opening the door to explore big-picture questions of telomeres and telomerase evolution.

PUBLICATIONS:

• Mefford, MA, Zappulla, DC. 2015. Physical connectivity mapping by circular permutation of human telomerase RNA reveals regions critical for activity and processivity. MCB 36(2):251-61.
• Fica SM*, Mefford MA*, Piccirilli JA, Staley JP. 2014. Evidence for a group II intron-like catalytic triplex in the spliceosome. NSMB 21(5):464-71 *Co-first authors
• Mefford MA, Rafiq Q, Zappulla DC. 2013. RNA connectivity requirements between conserved elements in the core of the yeast telomerase RNP. EMBO Journal 32(22):2990-2993.
• Fica SM, Small EC, Mefford MA, Staley JP. 2013. Mechanistic insights into mammalian pre-mRNA splicing. In Post-transcriptional Gene Regulation: RNA Processing in Eukaryotes, J.Y. WE, ed. Weinheim, Germany: Wiley VCH Verlag GmbH & Co. KGaA, pp. 133-161.
• Mefford MA, Staley JP. 2009. Evidence that U2/U6 helix I promotes both catalytic steps of pre-mRNA splicing and rearranges in between these steps. RNA 5(7):1386-1397.
• Hilliker AK, Mefford MA, Staley JP. 2007. U2 toggles iteratively between the stem IIa and stem IIc conformations to promote pre-mRNA splicing. Genes and Development 21(7), 821-834.