SUPV3L1 HELICASE KNOCKOUT MOUSE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We propose to address the function of the Supv3L1 DNA/RNA helicase in the mouse. The Supv3L1 helicase was initially described to be localized in mitochondria, however, more recent analysis in human cells indicates that the gene product is also present in the nucleus, where it may interact with proteins involved in DNA repair. In lower organisms the protein displays RNA unwinding activity and has been implicated in the regulation of RNA turnover in mitochondria. However, the human protein has recently been shown to also unwind double-stranded DNA, with one report even stating a preference for DNA, and special DNA structures such as forks. Supv3L1 belongs to the large family of DExD/H ATP-dependant helicases whose members include both DNA and RNA helicases. However, Supv3L1 genes of evolutionarily diverse organisms are more related to each other than to other members of the family, making inferences of biochemical or biological function based simply on phylogenetic consideration quite unreliable. In order to gain some insights into the function of this fascinating gene in higher organisms we propose to generate a knockout mouse for Supv3L1. We hypothesize that the Supv3L1 helicase may play a role in maintaining mitochondrial and/or nuclear genome integrity, and based on precedents in the literature we anticipate that disruption of theSupv3L1 gene may lead to a reduced lifespan, premature onset of aging-related phenotypes, and/or elevated neoplastic changes. Abundant evidence supports significant cross talk between nuclear and mitochondrial genomes. Nuclear genes encoding functions localized in mitochondria are involved in mtDNA and mtRNA metabolism, and mitochondrial damage or dysfunction has been linked with premature aging. On the other hand, several examples of nuclear DNA helicase dysfunction have been linked to tumor predisposition phenotypes.