Dissecting the role of human PPR motif proteins in mitochondrial gene expression
Item
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Title
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Dissecting the role of human PPR motif proteins in mitochondrial gene expression
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Identifier
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d_2009_2013:13c9be9d6516:10545
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identifier
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10947
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Creator
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Bangeranye, Catherine,
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Contributor
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Serafin Pinol-Roma
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Date
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2010
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Language
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English
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Publisher
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City University of New York.
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Subject
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Molecular biology | Biochemistry | Genetics | mitochondrial gene expression | Oxidative phosphorylation | PPR motif proteins
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Abstract
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Pentatricopeptide repeat (PPR) motif proteins constitute a growing superfamily of proteins that are broadly defined by the presence of one or more copies of a conserved 35 amino acid sequence, the PPR motif. They are particularly abundant in plants, and those whose function has been characterized have been implicated in several aspects of RNA metabolism in mitochondria and chloroplasts. In humans, PPR motif proteins are fewer in number. They include LRPPRC ( Leucine-Rich PPR-motif- Containing protein), an RNA-binding protein that is a component of nuclear ribonucleoprotein (RNP) complexes that contain spliced mRNAs. Most of the LRPPRC, however, localizes predominantly to mitochondria, where it binds polyadenylated RNAs. Mutations in the lrpprc gene cause cytochrome c oxidase deficiency in Leigh Syndrome (LSFC), which is accompanied by a decrease in COXI and COXIII mitochondrial mRNAs. Our hypothesis is that LRPPRC is an essential trans-acting factor in mitochondrial mRNA metabolism. In order to address the function of LRPPRC in mitochondria, we isolated LRPPRC-associated mitochondrial RNP complexes (mtRNPs). Analysis of isolated mtRNPs shows that the mitochondrially-encoded mRNAs associate with LRPPRC. A reduction in LRPPRC levels using RNAi causes a parallel reduction in steady-state levels of mitochondrially-encoded mRNAs, but not of nuclear-encoded mRNAs. Thus, LRPPRC is an important factor for mitochondrial gene expression and is necessary for the accumulation of the mitochondrial mRNAs to which it binds. Using LRPPRC as a paradigm, we sought and analyzed other members of the PPR motif family in humans. Four other human PPR-motif proteins, PTCD1, PTCD2, PTCD3 and PTCD4, also localize in mitochondria. Moreover, some of these proteins also bind RNA and exist in the same complexes as LRPPRC. This indicates that the human PTCD proteins, as is the case with LRPPRC, are also involved in mitochondrial RNA metabolism, pointing to PPR motif proteins in humans as a novel family of trans-acting factors in mitochondrial gene expression. These findings open the way for an expanded and more detailed understanding of human mitochondrial gene expression, and for an exploration of the potential involvement of human PPR motif proteins in mitochondrial diseases, as has already been determined for LRPPRC.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Biochemistry
