The role of LARP7 in RNA modification and its implicationfor spermatogenesis

La和La相关蛋白(LARPs)组成一个真核蛋白质家族，其特征是RNA结合La模块。因此，LARP家族的所有成员都参与了RNA代谢的各个方面，从转录和翻译控制到小的非编码RNA的稳定和陪伴。LARP7蛋白是该家族中普遍表达的成员，其功能是聚合酶II(POL II)基因的负转录调节因子。它通过7SK RNP颗粒起作用，7SK RNP颗粒通过隔离正转录延伸因子b(P-TEFb)来控制转录延伸。因此，POL II的磷酸化和转录延伸被阻止。与这种抗增殖活性一致的是，已有研究表明，功能LARP7水平的降低会导致各种类型的癌症。然而，LARP7突变也与以生长受限和核仁应激为特征的疾病有关，如原始侏儒症(Alazami综合征)，这增加了LARP7可能具有尚未确定的额外功能的可能性。我们最近观察到，LARP7蛋白在精子发生过程中急剧上调，而其主要细胞RNA配体7SK的水平保持不变。这表明LARP7可能针对其他RNA和途径，为了支持这一概念，我们发现了LARP7在修改与前mRNA剪接机制有关的RNA方面的功能的生化证据。在这次中德合作中，我们的目标是研究新发现的LARP7功能的生化基础及其对生殖细胞发育的意义。我们实验室在RNA生物化学(GM和UF)和生殖细胞生物学(ML)方面的互补专业知识将促进这一多学科项目，并使人们不仅能够深入了解LARP7的基本细胞活动，而且还能够深入了解其在精子发生中的作用。

La and La-related proteins (LARPs) comprise a eukaryotic protein-family characterized by the RNA binding La module. Accordingly, all members of the LARP family have been implicated in diverse aspects of RNA metabolism ranging from transcriptional and translational control of mRNAs to stabilization and chaperoning of small non-coding RNAs. The LARP7 protein is a ubiquitously expressed member of this family that functions as negative transcriptional regulator of polymerase II (Pol II) genes. It acts through the 7SK RNP particle, which controls transcription elongation by sequestering the positive transcription elongation factor b (P-TEFb). As a consequence, Pol II phosphorylation and transcriptional elongation is prevented. In agreement with this anti-proliferation activity, it has been shown that reduced levels of functional LARP7 cause various types of cancers. However, LARP7 mutations have also been linked to diseases characterized by growth restrictions and nucleolar stress such as primordial dwarfism (Alazami syndrome), raising the possibility that LARP7 may have additional functions yet to be identified. We have recently observed that the LARP7 protein becomes drastically up-regulated during spermatogenesis whereas the level of 7SK, its main cellular RNA ligand remained unaltered. This suggests that LARP7 may target other RNAs and pathways and in support of this notion, we found biochemical evidence for a function of LARP7 in modification of RNAs linked to the pre-mRNA splicing machinery. In this Sino-German collaboration we aim to investigate the biochemical basis of the newly discovered function of LARP7 and its implication for germ cell development. The complementary expertise of our labs in RNA biochemistry (GM and UF) and germ cell biology (ML) will facilitate this multidisciplinary project and enable insights not only into a basic cellular activity of LARP7 but also its role in spermatogenesis.