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Full-Text Articles in Molecular Biology

Multiple Molecular Mechanisms Rescue Mtdna Disease In C. Elegans, Suraiya Haroon, Annie Li, Jaye L. Weinert, Clark Fritsch, Nolan G. Ericson, Jasmine Alexander-Floyd, Bart P. Braeckman, Cole M. Haynes, Jason H. Bielas, Tali Gidalevitz, Marc Vermulst Mar 2018

Multiple Molecular Mechanisms Rescue Mtdna Disease In C. Elegans, Suraiya Haroon, Annie Li, Jaye L. Weinert, Clark Fritsch, Nolan G. Ericson, Jasmine Alexander-Floyd, Bart P. Braeckman, Cole M. Haynes, Jason H. Bielas, Tali Gidalevitz, Marc Vermulst

University of Massachusetts Medical School Faculty Publications

Genetic instability of the mitochondrial genome (mtDNA) plays an important role in human aging and disease. Thus far, it has proven difficult to develop successful treatment strategies for diseases that are caused by mtDNA instability. To address this issue, we developed a model of mtDNA disease in the nematode C. elegans, an animal model that can rapidly be screened for genes and biological pathways that reduce mitochondrial pathology. These worms recapitulate all the major hallmarks of mtDNA disease in humans, including increased mtDNA instability, loss of respiration, reduced neuromuscular function, and a shortened lifespan. We found that these phenotypes could ...


The Complex Role Of Sequence And Structure In The Stability And Function Of The Tim Barrel Proteins, Yvonne H. Chan Nov 2017

The Complex Role Of Sequence And Structure In The Stability And Function Of The Tim Barrel Proteins, Yvonne H. Chan

GSBS Dissertations and Theses

Sequence divergence of orthologous proteins enables adaptation to a plethora of environmental stresses and promotes evolution of novel functions. As one of the most common motifs in biology capable of diverse enzymatic functions, the TIM barrel represents an ideal model system for mapping the phenotypic manifestations of protein sequence. Limits on evolution imposed by constraints on sequence and structure were investigated using a model TIM barrel protein, indole-3-glycerol phosphate synthase (IGPS). Exploration of fitness landscapes of phylogenetically distant orthologs provides a strategy for elucidating the complex interrelationship in the context of a protein fold.

Fitness effects of point mutations in ...


Systematic Experimental Determination Of Functional Constraints On Proteins And Adaptive Potential Of Mutations: A Dissertation, Li Jiang May 2016

Systematic Experimental Determination Of Functional Constraints On Proteins And Adaptive Potential Of Mutations: A Dissertation, Li Jiang

GSBS Dissertations and Theses

Sequence-function relationship is a fundamental question for many branches of modern biomedical research. It connects the primary sequence of proteins to the function of proteins and fitness of organisms, holding answers for critical questions such as functional consequences of mutations identified in whole genome sequencing and adaptive potential of fast evolving pathogenic viruses and microbes. Many different approaches have been developed to delineate the genotype-phenotype map for different proteins, but are generally limited by their throughput or precision. To systematically quantify the fitness of large numbers of mutations, I modified a novel high throughput mutational scanning approach (EMPIRIC) to investigate ...


Mutations In Conserved Residues Of The C. Elegans Microrna Argonaute Alg-1 Identify Separable Functions In Alg-1 Mirisc Loading And Target Repression, Anna Y. Zinovyeva, Samir Bouasker, Martin J. Simard, Christopher M. Hammell, Victor R. Ambros Apr 2014

Mutations In Conserved Residues Of The C. Elegans Microrna Argonaute Alg-1 Identify Separable Functions In Alg-1 Mirisc Loading And Target Repression, Anna Y. Zinovyeva, Samir Bouasker, Martin J. Simard, Christopher M. Hammell, Victor R. Ambros

Program in Molecular Medicine Publications

microRNAs function in diverse developmental and physiological processes by regulating target gene expression at the post-transcriptional level. ALG-1 is one of two Caenorhabditis elegans Argonautes (ALG-1 and ALG-2) that together are essential for microRNA biogenesis and function. Here, we report the identification of novel antimorphic (anti) alleles of ALG-1 as suppressors of lin-28(lf) precocious developmental phenotypes. The alg-1(anti) mutations broadly impair the function of many microRNAs and cause dosage-dependent phenotypes that are more severe than the complete loss of ALG-1. ALG-1(anti) mutant proteins are competent for promoting Dicer cleavage of microRNA precursors and for associating with and ...