title: Human non-synonymous single nucleotide polymorphisms can influence ubiquitin-mediated protein degradation.
abstract: Ubiquitin-mediated proteolysis plays a critical role in the degradation of proteins important in the cellular processes, such as cell cycle/division, differentiation and development, DNA repair, transcriptional regulation, and signaling. It is carried out by a complex cascade of enzymes that contain a high degree of specificity to motifs found in many proteins with rapid turnover. For example, the PEST motifs are hydrophilic stretches of amino acids that serve as signals for proteolytic degradation. In this study, we propose that amino acid altering non-synonymous single nucleotide polymorphisms (nsSNP) result in the abolishment or creation of putative PEST motifs, and thus lead to abnormal stabilization or degradation of the proteins. Using a web-based algorithm, PESTFind, we analyzed a total of 253 nsSNPs from proteins involved in cell cycle (n = 24), DNA repair (n = 128), and TGFbeta signaling pathway (n = 101). Fifteen nsSNPs were located within putative PEST sequences, and 9/15 (60%) either created or abolished these PEST motifs. PEST motifs were abolished in the presence of nsSNPs in CCND3, PMS2, POLE4, SITPEC, and PPARG and putative PEST motifs were created in NEIL2, BIRC4, MLL2, and PPP1R15A. Although experimental analyses are required to confirm these results, they suggest that nsSNPs can induce changes in ubiquitin-mediated protein degradation.
authors.affiliation: Fred A. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Sevtap
authors.initials: S
authors.lastname: Savas
authors.forename: Mehjabeen
authors.initials: M
authors.lastname: Shariff
authors.forename: Ian W
authors.initials: IW
authors.lastname: Taylor
authors.forename: Hilmi
authors.initials: H
authors.lastname: Ozcelik
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D004260:DNA Repair / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D051379:Mice; D015513:Oncogene Proteins / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D015513:Oncogene Proteins; D011506:Proteins; D014452:Ubiquitins