Kuchta Krzysztof, Muszewska Anna, Knizewski Lukasz, Steczkiewicz Kamil, Wyrwicz Lucjan S, Pawlowski Krzysztof, Rychlewski Leszek, Ginalski Krzysztof
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.
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.
Nucleic Acids Res. 2016 May 5;44(8):3534-48. doi: 10.1093/nar/gkw222. Epub 2016 Apr 7.
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.
FAM46蛋白在所有已知动物基因组中都有编码，属于核苷酸转移酶（NTase）折叠超家族。人类的四种FAM46旁系同源物（FAM46A、FAM46B、FAM46C、FAM46D）都被认为与多种疾病有关，其中FAM46C被报道为多发性骨髓瘤的致病驱动因素；然而，它们的确切功能仍然未知。通过综合运用各种生物信息学分析（如结构域结构、细胞定位）以及详尽的文献和数据库搜索（如表达谱、蛋白质相互作用分子），我们将FAM46蛋白归类为活性非经典聚腺苷酸聚合酶，这类酶可修饰胞质和/或核RNA的3'末端。因此，这些蛋白可能调节基因表达，并且可能在细胞分化过程中发挥关键作用。对具有PAP/OAS1 SBD结构域的已知NTase的序列和结构多样性进行详细分析，并结合最先进的比较建模，使我们能够确定负责催化和底物结合的潜在活性位点残基。我们还探究了在人类癌症中发现的单点突变的作用，并提出FAM46基因可能参与包括肺癌、结直肠癌、肝细胞癌、头颈癌、尿路上皮癌、子宫内膜癌和肾乳头状癌以及黑色素瘤在内的其他主要恶性肿瘤的发生发展。鉴定这些参与真核生物RNA代谢的新型酶可能会指导对它们的进一步功能研究。
