RAB6C is a retrogene that encodes a centrosomal protein involved in cell cycle progression.
Rab-GTPases are key regulators of membrane transport, and growing evidence indicates that their expression levels are altered in certain human malignancies, including cancer. Rab6C, a newly identified Rab6 subfamily member, has attracted recent attention because its reduced expression might confer a selective advantage to drug-resistant breast cancer cells. Here, we report that RAB6C is a primate-specific retrogene derived from a RAB6A' transcript. RAB6C is transcribed in a limited number of human tissues including brain, testis, prostate, and breast. Endogenous Rab6C is considerably less abundant and has a much shorter half-life than Rab6A'. Comparison of the GTP-binding motifs of Rab6C and Rab6A', homology modeling, and GTP-blot overlay assays indicate that amino acid changes in Rab6C have greatly reduced its GTP-binding affinity. Instead, the noncanonical GTP-binding domain of Rab6C mediates localization of the protein to the centrosome. Overexpression of Rab6C results in G1 arrest, and its specific depletion generates tetraploid cells with supernumerary centrosomes, revealing a role of Rab6C in events related to the centrosome and cell cycle progression. Thus, RAB6C is a rare example of a recently emerged retrogene that has acquired the status of a new gene, encoding a functional protein with altered characteristics compared to Rab6A'.
Young
Joanne
J
Molecular Mechanisms of Intracellular Transport, CNRS, UMR144, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
Ménétrey
Julie
J
Goud
Bruno
B
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002460:Cell Line; D018385:Centrosome / Q000378:metabolism*; D005786:Gene Expression Regulation; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007438:Introns / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009928:Organ Specificity / Q000235:genetics; D011123:Polyploidy; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018626:Retroelements / Q000235:genetics*; D013045:Species Specificity; D014158:Transcription, Genetic; D020691:rab GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D012333:RNA, Messenger; C094135:Rab6 protein; D018626:Retroelements; D006160:Guanosine Triphosphate; C417211:RAB6C protein, human; D020691:rab GTP-Binding Proteins