Defining the role of protein N-terminal acetylation during female germ-line development.
N-terminal acetylation is an enzyme-catalyzed reaction in which the protein alpha-amino group accepts the acetyl group from acetyl-CoA (Starheim et al., 2009). The addition of the acetyl group may influence the protein function, stability, interaction with other molecules, cellular localization and secretion, or other subsequent posttranslational modifications. N-terminal acetylation is catalyzed by a highly conserved family of N-terminal acetyltransferases (NATs) (Starheim et al., 2009). N-terminal acetyltransferase activity is mostly mediated by six distinct but highly conserved complexes (NatA to NatF) that have distinct subunits and substrate specificities. NATs are frequently misregulated in advanced and highly aggressive tumors (Kalvik and Arnesen, 2012).
The gene separation anxiety (san) is required in Drosophila and human HeLa cells for centromeric sister chromatid cohesion (Hou et al., 2007; Williams et al., 2003). san is also important for chromosome condensation/ resolution, which suggests that this gene is likely to have a more general mitotic function (Pimenta-Marques et al., 2008). san encodes a conserved N-terminal acetyltransferase (Naa50), which is the catalytic subunit of NatE. We hypothesize that Naa50/ San regulates the activity (or stability) of an unknown protein(s) whose function is crucial for mitosis. Surprisingly, whereas Naa50/ San was required in the soma for chromosome segregation, Drosophila female germ-line stem cells mutant for san showed no obvious mitotic defects (Pimenta-Marques et al., 2008). We hypothesized the existence of another NAT that was specifically redundant with Naa50/ San within the female germ-line. Yet, characterization of the closely related paralogue, Naa60, has failed to detect any redundancy within the female germ-line (Van Damme et al., 2011) (unpublished data).
Ongoing research work in our laboratory has already define the mitotic function of San (unpublished data) and we are currently trying to molecularly define its function. This post-doctoral research proposal aims not only to participate in the ongoing research projects related with the mitotic functions of San and other NATs, but also trying to understand why is N-terminal acetylation differentially required during development of the female germ-line. We hypothesize the differential regulation of this co-translational protein modification is important for germ line development, the only truly immortal and totipotent cell lineage.
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This project will be mostly development in the Medical Department of the University of Algarve. Nevertheless, the candidate should be prepared to do short-term visits to the laboratory of our ongoing collaborator (Thomas Arnesen, Norway), and if needed, to spend a few days in Lisbon.