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The FASTK family of proteins: emerging regulators of mitochondrial RNA biology.

ABSTRACT: The FASTK family proteins have recently emerged as key post-transcriptional regulators of mitochondrial gene expression. FASTK, the founding member and its homologs FASTKD1-5 are architecturally related RNA-binding proteins, each having a different function in the regulation of mitochondrial RNA biology, from mRNA processing and maturation to ribosome assembly and translation. In this review, we outline the structure, evolution and function of these FASTK proteins and discuss the individual role that each has in mitochondrial RNA biology. In addition, we highlight the aspects of FASTK research that still require more attention.

SUBMITTER: Jourdain AA

PROVIDER: S-EPMC5737537 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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The FASTK family of proteins: emerging regulators of mitochondrial RNA biology.

Jourdain Alexis A AA Popow Johannes J de la Fuente Miguel A MA Martinou Jean-Claude JC Anderson Paul P Simarro Maria M

Nucleic acids research 20171101 19

The FASTK family proteins have recently emerged as key post-transcriptional regulators of mitochondrial gene expression. FASTK, the founding member and its homologs FASTKD1-5 are architecturally related RNA-binding proteins, each having a different function in the regulation of mitochondrial RNA biology, from mRNA processing and maturation to ribosome assembly and translation. In this review, we outline the structure, evolution and function of these FASTK proteins and discuss the individual role ...[more]

PMID: 29036396

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Project description:Transcription of the human mitochondrial genome and correct processing of the two long polycistronic transcripts are crucial for oxidative phosphorylation. According to the tRNA punctuation model, nucleolytic processing of these large precursor transcripts occurs mainly through the excision of the tRNAs that flank most rRNAs and mRNAs. However, some mRNAs are not punctuated by tRNAs, and it remains largely unknown how these non-canonical junctions are resolved. The FASTK family proteins are emerging as key players in non-canonical RNA processing. Here, we have generated human cell lines carrying single or combined knockouts of several FASTK family members to investigate their roles in non-canonical RNA processing. The most striking phenotypes were obtained with loss of FASTKD4 and FASTKD5 and with their combined double knockout. Comprehensive mitochondrial transcriptome analyses of these cell lines revealed a defect in processing at several canonical and non-canonical RNA junctions, accompanied by an increase in specific antisense transcripts. Loss of FASTKD5 led to the most severe phenotype with marked defects in mitochondrial translation of key components of the electron transport chain complexes and in oxidative phosphorylation. We reveal that the FASTK protein family members are crucial regulators of non-canonical junction and non-coding mitochondrial RNA processing. Author summary As a legacy of their bacterial origin, mitochondria have retained their own genome with a unique gene expression system. All mitochondrially encoded proteins are essential components of the respiratory chain. Therefore, the mitochondrial gene expression is crucial for their iconic role as the ‘powerhouse of the cell’–ATP synthesis through oxidative phosphorylation. Consistently, defects in enzymes involved in this gene expression system are a common source of incurable inherited metabolic disorders, called mitochondrial diseases. The human mitochondrial transcription generates long polycistronic transcripts that carry information for multiple genes, so that the expression level of each gene is mainly regulated through post-transcriptional events. The polycistronic transcript first undergoes RNA processing, where individual mRNA, rRNA, and tRNA are cleaved off. However, its entire molecular mechanism remains unclear, and in particular, ‘non-canonical’ RNA processing has been poorly understood. To address this question, we studied the FASTK family proteins, emerging key mitochondrial post-transcriptional regulators. We generated different human cell lines carrying single or combined disruption of FASTKD3, FASTKD4, and FASTKD5 genes, and analyzed them using biochemical and genetic approaches. We show that the FASTK family members fine-tune the processing of both ‘canonical’ and ‘non-canonical’ mitochondrial RNA junctions.

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The FASTK family of proteins: emerging regulators of mitochondrial RNA biology.

Publications

The FASTK family of proteins: emerging regulators of mitochondrial RNA biology.

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