The role of LARP7 in RNA modification and its implicationfor spermatogenesis

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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.