SUPV3L1 HELICASE KNOCKOUT MOUSE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们建议研究Supv3L1 DNA/RNA解旋酶在小鼠中的功能。Supv3L1解旋酶最初被描述为定位于线粒体，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，该蛋白质显示出RNA解旋活性，并参与调节线粒体中的RNA周转。然而，人类蛋白质最近被证明也可以解开双链DNA，其中一份报告甚至指出，人们更喜欢DNA和特殊的DNA结构，如叉子。Supv3L1属于依赖DExD/H ATP的解旋酶大家族，其成员包括DNA解旋酶和RNA解旋酶。然而，进化上不同的生物体中的Supv3L1基因彼此之间的亲缘关系比与家族其他成员的亲缘关系更大，这使得单纯基于系统发育考虑的生化或生物学功能的推断是不可靠的。为了深入了解这一令人着迷的基因在高等生物体中的功能，我们提议为Supv3L1制造一个基因敲除小鼠。我们假设Supv3L1解旋酶可能在维持线粒体和/或核基因组的完整性方面发挥作用，并且根据文献中的先例，我们预计Supv3L1基因的破坏可能导致寿命缩短、衰老相关表型的过早发生和/或肿瘤改变的增加。大量证据支持核基因组和线粒体基因组之间存在显著的串扰。编码线粒体功能的核基因参与mtDNA和mtRNA的代谢，线粒体的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与肿瘤易感性表型有关。

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.