Inhaltszusammenfassung

Germ cells are responsible for the transmission of genetic information across generations. Hence, genomic instability in these cells can come at the cost of individual fertility and the fitness of a species. In animals, the RNAi-like Piwi-pathway has evolved to counteract the activity of one of the biggest threats to genome stability, Transposable Elements (TEs). In this pathway, Piwi-clade argonaute proteins use Piwi-Interacting RNAs (piRNAs) to recognize and induce the silencing of genome p...Germ cells are responsible for the transmission of genetic information across generations. Hence, genomic instability in these cells can come at the cost of individual fertility and the fitness of a species. In animals, the RNAi-like Piwi-pathway has evolved to counteract the activity of one of the biggest threats to genome stability, Transposable Elements (TEs). In this pathway, Piwi-clade argonaute proteins use Piwi-Interacting RNAs (piRNAs) to recognize and induce the silencing of genome parasites such as TEs. The piRNAs of Caenorhabditis elegans are known as 21U RNAs. This organism has the astonishing repertoire of around 30,000 different 21U RNAs, which are loaded into the C. elegans Piwi argonaute PRG-1. This argonaute uses these 21 nucleotide long small RNAs to recognize and induce the silencing of genomic parasites. Recognition by PRG-1 induces silencing and initiates an epigenetic silencing memory that can be parentally perpetuated for an indefinite number of generations. This extraordinarily effective silencing is supported by both transcript and chromatin silencing. The 21U RNAs are transcribed as precursors by RNA Polymerase II. These contain a 5’end Cap and flanking sequences that need to be removed before PRG-1 loading. The process by which this maturation is achieved is largely unknown, as is the molecular machinery involved. In this work, I search and find novel machinery required for 21U RNA processing. I started by focusing on the 21U RNA biogenesis factor PID-1 (piRNA-induced silencing defective 1). I found that this protein is part of a larger, novel protein complex, I named PETISCO (PID-3, ERH-2, TOFU-6 and IFE-3 Small RNA COmplex), that is also required for 21U RNA biogenesis. This complex binds the 5’ Caps of 21U RNA precursors via IFE-3, a eIF4E-family protein, typically required for mRNA translation in other organisms. Not only did I resolve the architecture of PETISCO, I also found that this complex is required for a second function, essential for embryonic development. This function is guided by the protein TOST-1 (Twenty One u AntagoniST 1), which I propose binds PETISCO interchangeably with PID-1. Together these two proteins independently guide the two functions of PETISCO: 21U RNA biogenesis and embryonic viability. Finally, I propose that the embryonic requirement of PETISCO is connected to Splice Leader snRNA and core histone mRNA regulation and discuss how this relation may have evolved.» weiterlesen» einklappen

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DDC Sachgruppe:
Biowissenschaften, Biologie