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    • We also identified a role for the transcription factor p

    2019-07-19

    We also identified a role for the transcription factor p53 in the regulation of the Crm1 promoter. p53 can activate or repress the transcription of target genes. While activation generally occurs through binding of p53 to its consensus binding site in the promoter region of target genes, for example, p21, GADD45 and 14-3-3, it can repress promoters that lack a consensus p53 binding site. This can occur via several mechanisms; either through its interference with the functions of other DNA-binding transcriptional activators, or through its interference with components of the basal transcription machinery, or through its recruiting chromatin-modifying factors such as histone deacetylases (HDAC) to promoter regions, thereby reducing promoter accessibility to the transcriptional machinery [50]. p53 target genes repressed via these mechanisms include cyclin B1 [51], cdc2 [52], BRCA2 [53], survivin [54], hsp70 [55], amongst others. In the case of p53 interfering with other transcriptional activators, it is reported that p53 can interact specifically with NFY and Sp1 proteins, hampering the NFY- and Sp1-dependent recruitment of the general transcriptional machinery to the promoter region of target genes [25], [51], [52], [54], [55]. In this study we provide evidence that p53 represses the Crm1 promoter, and that repression occurs predominantly via interference with NFY. Our results suggest that p53 can interfere with NFY-regulated Crm1 expression under conditions of DNA damage by directly interfering with NFY binding and in this way result in promoter repression. Our results also suggest that p53 may complex with NFY and in this way mediate promoter repression. There is evidence in the literature that under conditions of DNA damage, the binding of p53 to certain promoters results in 11-dUTP remodelling which associates with transcriptional repression [56]. We speculate in the case of the Crm1 promoter that p53 possibly promotes chromatin remodelling; only when the promoter is in an active state (and bound by NFY) hence the dependence on NFY for repression, and that this results in a loss of NFY binding to the promoter as observed in ChIP analysis. Further work, however, is required to investigate the exact mechanism of repression by p53. While we have shown a role for p53 in negatively regulating the Crm1 promoter, it is also well understood that Crm1 plays a role in the negative regulation of p53 activity by mediating its export from the nucleus to the cytoplasm [57]. Hence it appears that Crm1 and p53 could share a complex regulatory loop, whereby p53 represses Crm1 promoter activity in response to DNA damage, and the low levels of Crm1 that result could possibly lead to a decreased rate of export of p53 into the cytoplasm, resulting in increased p53 function. This could be one of the reasons why during tumourigenesis the cell must abrogate p53 function and/or upregulate Crm1 transcription in order to evade p53 and allow for uncontrolled proliferation. The following are the supplementary materials related to this article
    Funding This work was supported by grants from the University of Cape Town, the Carnegie Corporation of New York, CANSA, and the Medical Research Council of South Africa.
    Introduction The nuclear pore complex (NPC) is a giant protein complex embedded between the inner and the outer nuclear membrane that allows transport of large proteins and ribonucleoprotein particles into and out of the nucleus. At the same time, it restricts translocation by diffusion of small proteins and, thus, functions as a selective gate (Cook et al., 2007, Wente and Rout, 2010). The majority of actively translocated proteins interact with receptor proteins of the importin β superfamily, also referred to as karyopherins or importins/exportins. They mediate the translocation by binding to nucleoporins (Nups), the proteins forming the NPC. Another common binding partner of all karyopherins is the GTPase Ran. In nuclear import, binding of RanGTP to the importin results in dissociation of the import complex in the nucleus and to its release from a nucleoporin-binding site. In nuclear export, RanGTP is part of the export complex and accompanies it to the cytoplasmic side of the NPC. With RanGTP and nucleoporins as common binding partners, importins and exportins share many structural features. Generally, karyopherins are characterized by a modular architecture with a variable number of tandem HEAT repeats. Each HEAT repeat consists of two antiparallel α helices (A and B helix), connected by a short loop (Cook et al., 2007).