title: Terminal uridyltransferase enzyme Zcchc11 promotes cell proliferation independent of its uridyltransferase activity.
abstract: Zcchc11 is a uridyltransferase protein with enzymatic activity directed against diverse RNA species. On the basis of its known uridylation targets, we hypothesized that Zcchc11 might regulate cell proliferation. Confirming this, loss-of-function and complementary gain-of-function experiments consistently revealed that Zcchc11 promotes the transition from G(1) to S phase of the cell cycle. This activity takes place through both Rb-dependent and Rb-independent mechanisms by promoting the expression of multiple G(1)-associated proteins, including cyclins D(1) and A and CDK4. Surprisingly, a Zcchc11 construct with point mutations inactivating the uridyltransferase domain enhanced cell proliferation as effectively as wild-type Zcchc11. Furthermore, truncated mutant constructs revealed that the cell cycle effects of Zcchc11 were driven by the N-terminal region of the protein that lacks the RNA-binding domains and uridyltransferase activity of the full protein. Therefore, the N-terminal portion of Zcchc11, which lacks nucleotidyltransferase capabilities, is biologically active and mediates a previously unrecognized role for Zcchc11 in facilitating cell proliferation.
authors: Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts 02118; Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, Massachusetts 02115.
authors: Matthew T
authors: MT
authors: Blahna
authors: Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts 02118.
authors: Matthew R
authors: MR
authors: Jones
authors: Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts 02118.
authors: Lee J
authors: LJ
authors: Quinton
authors: Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts 02118.
authors: Kori Y
authors: KY
authors: Matsuura
authors: Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts 02118. Electronic address: jmizgerd@bu.edu.
authors: Joseph P
authors: JP
authors: Mizgerd
mesh_terms: D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D042783:Endothelial Cells; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D017434:Protein Structure, Tertiary; D012313:RNA / Q000737:chemistry; D016160:Retinoblastoma Protein / Q000737:chemistry; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; D016160:Retinoblastoma Protein; C511130:TUT4 protein, human; D012313:RNA; D018844:Cyclin-Dependent Kinases