New paradigms for regulation of human mitochondrial transcription (94.2)

Abstract

Transcription of human mitochondrial DNA (mtDNA) is directed by three promoters: light‐strand promoter (LSP); heavy‐strand promoter 1 (HSP1) and HSP2. Initiation from all promoters requires the mitochondrial RNA polymerase (POLRMT) and mitochondrial transcription factor B2 (TFB2M). Initiation from all promoters is now known to be differentially regulated by the concentration of mitochondrial transcription factor A (TFAM). Full activation of HSP1 requires sequences upstream of the sequences thought to be necessary and sufficient for HSP1 utilization. These “upstream sequences” are highly polymorphic in the human population and are also sites of somatic mutations linked to disease. The contribution of these somatic mutations to the disease phenotypes is not know. The primary obstacle to assessing the causal or consequential relationship between somatic mutations in mtDNA and disease is the retrospective nature of the analysis. In collaboration with the Ridky lab (Nat Med. 2010 Dec; 16(12):1450‐5), we have performed a prospective analysis using squamous cell carcinomas established ex vivo. We observe mutations reminiscent of those observed retrospectively. The implications of this system and our findings on the consequence of these mutations for misregulated mitochondrial transcription in cancer will be discussed.