Alternative titles; symbols
HGNC Approved Gene Symbol: MAF1
Cytogenetic location: 8q24.3 Genomic coordinates (GRCh38) : 8:144,104,461-144,107,611 (from NCBI)
Pluta et al. (2001) identified orthologs of yeast Maf1 in human, animals, plants, and lower eukaryotes, but not in prokaryotes. Human MAF1 contains 3 regions conserved in Maf1 proteins, followed by an acidic C-terminal tail. The second conserved region includes a putative nuclear targeting signal.
In yeast, Maf1 affects tRNA suppressor efficiency and interacts with RNA polymerase III (pol III; see 606007). Pluta et al. (2001) found that tRNA levels were elevated in Maf1 mutant yeast cells. The in vitro rate of pol III RNA synthesis was significantly increased in Maf1 mutant cell extracts. Pluta et al. (2001) concluded that Maf1 is a repressor of pol III synthesis.
Upadhya et al. (2002) found that yeast signaling pathways activated in response to rapamycin-induced nutrient limitation, DNA damage, and secretory defects, as well as the normal yeast growth cycle, required Maf1 to affect pol III transcriptional repression. They identified TFIIIB (see 607013) as a target of Maf1-dependent repression.
Oficjalska-Pham et al. (2006) and Roberts et al. (2006) found that yeast Maf1 was phosphorylated under favorable conditions, whereas diverse unfavorable conditions led to rapid Maf1 dephosphorylation, nuclear localization, and physical association of dephosphorylated Maf1 with pol III.
Using immunoprecipitation analysis, Reina et al. (2006) showed that human MAF1 interacted with pol III. Protein pull-down assays showed that MAF1 interacted strongly with the pol I (see 602000) and pol III subunit RPAC2 (POLR1D; 613715). It interacted more weakly with the pol III subunit RPC1 (POLR3A) and with BRAF1 (164757). Mutation analysis revealed that the N-terminal region of MAF1 interacted with the pol III subunits and that the second conserved domain, the B box, interacted with BRAF1. MAF1 did not interact with promoter-bound pol III. Knockdown of MAF1 via RNA interference increased the levels of precursor tRNAs in HEK293 cells and IMR-90 human lung fibroblasts. Cell stress in HEK293 or IMR-90 cells reduced the level of MAF1 phosphorylation, and dephosphorylation of MAF1 was required for pol III repression following cell stress.
Johnson et al. (2007) showed that human MAF1 negatively regulated transcription by all 3 nuclear RNA polymerases. Changes in MAF1 expression affected pol I- and pol III-dependent transcription in human glioblastoma cell lines. These effects were mediated, in part, through the ability of MAF1 to repress transcription of TATA-binding protein (TBP; 600075). MAF1 targeted an ELK1 (311040)-binding site in the TBP promoter, and binding at this site was reciprocal with that of ELK1. Similarly, MAF1 occupancy of pol III genes was inversely correlated with that of the initiation factor TFIIIB and pol III. The phenotypic consequences of reducing MAF1 expression included changes in cell morphology and accumulation of actin stress fibers, whereas MAF1 overexpression suppressed anchorage-independent growth.
Vannini et al. (2010) found that dephosphorylated yeast Maf1 bound the Pol III clamp region and rearranged the Pol III subunits involved in promoter recognition and initiation at the active center cleft. Binding impaired recruitment of Pol III to a complex of initiation factors and Pol III promoter DNA. Phosphorylation of a mobile sequence of Maf1 masked a nuclear localization signal, and dephosphorylation following cell stress was predicted to permit Maf1 nuclear import. This mechanism appeared to be conserved between yeast and human MAF1, although the phosphorylation site within the mobile sequence differed.
Hartz (2011) mapped the MAF1 gene to chromosome 8q24.3 based on an alignment of the sequence (GenBank AL136937) with the genomic sequence (GRCh37).
Hartz, P. A. Personal Communication. Baltimore, Md. 7/13/2011.
Johnson, S. S., Zhang, C., Fromm, J., Willis, I. M., Johnson, D. L. Mammalian Maf1 is a negative regulator of transcription by all three nuclear RNA polymerases. Molec. Cell 26: 367-379, 2007. [PubMed: 17499043] [Full Text: https://doi.org/10.1016/j.molcel.2007.03.021]
Oficjalska-Pham, D., Harismendy, O., Smagowicz, W. J., Gonzalez de Peredo, A., Boguta, M., Sentenac, A., Lefebvre, O. General repression of RNA polymerase III transcription is triggered by protein phosphatase type 2A-mediated dephosphorylation of Maf1. Molec. Cell 22: 623-632, 2006. [PubMed: 16762835] [Full Text: https://doi.org/10.1016/j.molcel.2006.04.008]
Pluta, K., Lefebvre, O., Martin, N. C., Smagowicz, W. J., Stanford, D. R., Ellis, S. R., Hopper, A. K., Sentenac, A., Boguta, M. Maf1p, a negative effector of RNA polymerase III in Saccharomyces cerevisiae. Molec. Cell. Biol. 21: 5031-5040, 2001. [PubMed: 11438659] [Full Text: https://doi.org/10.1128/MCB.21.15.5031-5040.2001]
Reina, J. H., Azzouz, T. N., Hernandez, N. Maf1, a new player in the regulation of human RNA polymerase III transcription. PLos One 1: e134, 2006. Note: Electronic Article. [PubMed: 17205138] [Full Text: https://doi.org/10.1371/journal.pone.0000134]
Roberts, D. N., Wilson, B., Huff, J. T., Stewart, A. J., Cairns, B. R. Dephosphorylation and genome-wide association of Maf1 with Pol III-transcribed genes during repression. Molec. Cell 22: 633-644, 2006. [PubMed: 16762836] [Full Text: https://doi.org/10.1016/j.molcel.2006.04.009]
Upadhya, R., Lee, J., Willis, I. M. Maf1 is an essential mediator of diverse signals that repress RNA polymerase III transcription. Molec. Cell 10: 1489-1494, 2002. [PubMed: 12504022] [Full Text: https://doi.org/10.1016/s1097-2765(02)00787-6]
Vannini, A., Ringel, R., Kusser, A. G., Berninghausen, O., Kassavetis, G. A., Cramer, P. Molecular basis of RNA polymerase III transcription repression by Maf1. Cell 143: 59-70, 2010. [PubMed: 20887893] [Full Text: https://doi.org/10.1016/j.cell.2010.09.002]