title: FAM46 proteins are novel eukaryotic non-canonical poly(A) polymerases.
abstract: FAM46 proteins, encoded in all known animal genomes, belong to the nucleotidyltransferase (NTase) fold superfamily. All four human FAM46 paralogs (FAM46A, FAM46B, FAM46C, FAM46D) are thought to be involved in several diseases, with FAM46C reported as a causal driver of multiple myeloma; however, their exact functions remain unknown. By using a combination of various bioinformatics analyses (e.g. domain architecture, cellular localization) and exhaustive literature and database searches (e.g. expression profiles, protein interactors), we classified FAM46 proteins as active non-canonical poly(A) polymerases, which modify cytosolic and/or nuclear RNA 3' ends. These proteins may thus regulate gene expression and probably play a critical role during cell differentiation. A detailed analysis of sequence and structure diversity of known NTases possessing PAP/OAS1 SBD domain, combined with state-of-the-art comparative modelling, allowed us to identify potential active site residues responsible for catalysis and substrate binding. We also explored the role of single point mutations found in human cancers and propose that FAM46 genes may be involved in the development of other major malignancies including lung, colorectal, hepatocellular, head and neck, urothelial, endometrial and renal papillary carcinomas and melanoma. Identification of these novel enzymes taking part in RNA metabolism in eukaryotes may guide their further functional studies.
authors.affiliation: Laboratory of Bioinformatics and Systems Biology, Centre of New Technologies, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw, Poland College of Inter-Faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, Banacha 2C, 02-097 Warsaw, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kuchta
authors.affiliation: Laboratory of Bioinformatics and Systems Biology, Centre of New Technologies, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw, Poland Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Muszewska
authors.affiliation: Laboratory of Bioinformatics and Systems Biology, Centre of New Technologies, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw, Poland.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Knizewski
authors.affiliation: Laboratory of Bioinformatics and Systems Biology, Centre of New Technologies, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw, Poland.
authors.forename: Kamil
authors.initials: K
authors.lastname: Steczkiewicz
authors.affiliation: Laboratory of Bioinformatics and Biostatistics, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, WK Roentgena 5, 02-781 Warsaw, Poland.
authors.forename: Lucjan S
authors.initials: LS
authors.lastname: Wyrwicz
authors.affiliation: Department of Experimental Design and Bioinformatics, Warsaw University of Life Sciences, Nowoursynowska 166, 02-787 Warsaw, Poland.
authors.forename: Krzysztof
authors.identifier: 0000-0002-5367-0935
authors.initials: K
authors.lastname: Pawlowski
authors.affiliation: BioInfoBank Institute, Limanowskiego 24A, 60-744 Poznan, Poland.
authors.forename: Leszek
authors.initials: L
authors.lastname: Rychlewski
authors.affiliation: Laboratory of Bioinformatics and Systems Biology, Centre of New Technologies, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw, Poland kginal@cent.uw.edu.pl.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Ginalski
mesh_terms: D020134:Catalytic Domain / Q000235:genetics*; D019295:Computational Biology; D030541:Databases, Genetic; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics*; D009713:Nucleotidyltransferases; D011062:Polynucleotide Adenylyltransferase / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; D011506:Proteins; D009713:Nucleotidyltransferases; C000621064:TENT5B protein, human; C000621065:TENT5C protein, human; D011062:Polynucleotide Adenylyltransferase; C466099:TENT5A protein, human; C545355:TENT5D protein, human