Mechanistic analysis of piRNA precursor nuclear export

Nuclear export of newly synthesized RNA to the cytoplasm is an essential step in eukaryotic gene expression, yet the participating proteins and their interplay remain poorly understood at the molecular level.

Here, I propose to study RNA export of a family of long non-coding RNAs to elucidate fundamental principles underlying the regulated assembly of export-competent RNPs. I will focus on the precursors of piRNAs, a class of small regulatory RNAs.

These transcripts are generated by RNA Polymerase II from heterochromatic, transposon-rich loci and are processed into piRNAs in the cytoplasm to specify transposon silencing.

Notably, piRNA precursors violate mRNA quality control hallmarks and thus have to bypass degradation in the nucleus for their export.

For this a specialized pathway evolved, combining canonical mRNA export factors with novel or neo-functionalized components.

I propose a holistic approach combining quantitative biochemistry, structural biology and genetics to integrate known and novel components into a coherent model of piRNA-precursor export.

I aim at understanding (1) the recruitment of export factors to sites of transcription, and (2) the nature and regulation of a nuclear piRNP complex consisting of piRNA factors and the canonical mRNA export components UAP56 and THO complex. The molecular function and regulation of these highly conserved proteins is poorly understood.

Elucidating how piRNA-precursor export hijacks canonical RNA export factors to avoid mRNA quality control thus holds great promise to uncover general principles of RNA cargo loading onto NXF family proteins and the molecular principles of nuclear RNA export.