Abstract
BackgroundProtein phosphatase 1 (PP1) is involved in diverse cellular processes, and is targeted to substrates via interaction with many different protein binding partners. PP1 catalytic subunits (PP1c) fall into PP1α and PP1β subfamilies based on sequence analysis, however very few PP1c binding proteins have been demonstrated to discriminate between PP1α and PP1β.ResultsURI (unconventional prefoldin RPB5 interactor) is a conserved molecular chaperone implicated in a variety of cellular processes, including the transcriptional response to nutrient signalling and maintenance of DNA integrity. We show that Drosophila Uri binds PP1α with much higher affinity than PP1β, and that this ability to discriminate between PP1c forms is conserved to humans. Most Uri is cytoplasmic, however we found some protein associated with active RNAPII on chromatin. We generated a uri loss of function allele, and show that uri is essential for viability in Drosophila. uri mutants have transcriptional defects, reduced cell viability and differentiation in the germline, and accumulate DNA damage in their nuclei.ConclusionUri is the first PP1α specific binding protein to be described in Drosophila. Uri protein plays a role in transcriptional regulation. Activity of uri is required to maintain DNA integrity and cell survival in normal development.
Highlights
Protein phosphatase 1 (PP1) is involved in diverse cellular processes, and is targeted to substrates via interaction with many different protein binding partners
Type 1 protein phosphatase (PP1) is one of the major serine/threonine phosphatase classes found in all eukaryotic cells
CG11416 has been described as the Drosophila homologue of URI since the Nterminal region contains a Prefoldin domain, most similar to that of human URI (RMP, NNX3), and the C-terminus contains a short region of homology termed the URI-Box (Full alignment shown in [22], supplementary material)
Summary
Protein phosphatase 1 (PP1) is involved in diverse cellular processes, and is targeted to substrates via interaction with many different protein binding partners. PP1 catalytic subunits (PP1c) fall into PP1α and PP1β subfamilies based on sequence analysis, very few PP1c binding proteins have been demonstrated to discriminate between PP1α and PP1β. Biochemical analysis of protein phosphatase activity led to the identification of distinct enzyme classes based on sensitivity to inhibitors, in vitro substrate specificity and cation requirements. Cloning of the catalytic subunits of PP1 (PP1c) revealed that there are distinct enzyme forms which had not been distinguished biochemically. Phylogenetic analysis has revealed that there is an evolutionarily conserved distinction between animal PP1α (human PP1α and γ; Drosophila PP1α87B, PP1α13C and PP1α96A) and PP1β (human PP1β or PP1δ; Drosophila PP1β9C) implying that the gene products have distinct biological functions despite their identical biochemical properties in vitro and >85% sequence iden-. PP1α87B and PP1β9C are both essential for viability, PP1α96A and PP1α13C are dispensable [1,2,4,5]
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