SUPV3L1 HELICASE KNOCKOUT MOUSE

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。我们建议解决Supv 3L 1 DNA/RNA解旋酶在小鼠中的功能。Supv 3L 1解旋酶最初被描述为位于线粒体中，然而，最近对人类细胞的分析表明，该基因产物也存在于细胞核中，在那里它可能与参与DNA修复的蛋白质相互作用。在低等生物中，该蛋白质显示RNA解旋活性，并参与线粒体中RNA周转的调节。然而，人类蛋白质最近被证明也可以解开双链DNA，有一份报告甚至指出了对DNA的偏好，以及特殊的DNA结构，如叉。Supv 3L 1属于DExD/HATP依赖性解旋酶大家族，其成员包括DNA和RNA解旋酶。然而，Supv 3L 1基因的进化上不同的生物更相关的彼此比其他成员的家庭，使推断的生化或生物功能的基础上简单的系统发育考虑相当不可靠。为了深入了解这个迷人的基因在高等生物中的功能，我们建议产生Supv 3L 1基因敲除小鼠。我们假设Supv 3L 1解旋酶可能在维持线粒体和/或核基因组完整性方面发挥作用，并且基于文献中的先例，我们预计Supv 3L 1基因的破坏可能导致寿命缩短、衰老相关表型过早发生和/或肿瘤变化升高。大量的证据支持细胞核和线粒体基因组之间的重要串扰。线粒体中编码功能的核基因参与mtDNA和mtDNA代谢，线粒体损伤或功能障碍与过早衰老有关。另一方面，核DNA解旋酶功能障碍的几个例子已经与肿瘤易感性表型相关联。

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.