Genomic instability

in the popular tale " Ozma of Oz, " Lyman Frank Baum describes the princess Langwidere, who is capable of interchanging her currently worn head with another one, using a collection of heads stored in a cabinet. Remarkably, she changes her character as well when putting a new head on her neck. in the December 15, 2012 issue of Cell Cycle, Kurt Engeland and colleagues report a similar phenomenon 1 with regard to a DNA-associated, transcription-regulatory complex of proteins, the DREAM/MMB complex. A central core of this complex, MuvB, binds to a DNA motif called CHR for cell cycle genes homology region. 2 in addition, the complex has facultative members. Either the B-Myb oncoprotein joins to activate transcription from the adjacent gene—this composition is termed MMB for Myb-MuvB. Alternatively, the retinoblastoma protein homolog p130, along with the prototype-repressive member of the E2F family, E2F4 and the auxiliary DNA-binding partner protein DP1, associate with MuvB to form an entity called DREAM for DP, RB-like, E2F and MuvB complex. This complex was first purified from Drosophila embryos 3 and then characterized in mammalian cells. 4 Exchanging the " head " of the complex in this way also changes its " character, " converting the transactivator MMB to the repressive DREAM complex. Strikingly, the new report shows how this re-association of the MMB/DREAM complex can be induced. Activating the tumor suppressor p53 drives the expression of the cyclin-dependent kinase p21/Cip1/Waf1/CDKN1A. This, in turn, leads to the hypophosphorylation of p130 and thereby enables its association with MuvB, replacing B-Myb and mediating Figure 1. p53-mediated gene repression. p53 reportedly can act as a repressor of genes by at least three mechanisms. The first one involves the association of p53 with the transcription factor complex NF-y, which, in turn, binds the CAAT box of promoter DNA. The two other mechanisms each depend on the transactivation of p21 by p53. p21 blocks cyclin-dependent kinases (CDKs), leading to the hypophosphorylation of retinoblastoma (Rb) family members. These then associate with E2F proteins. E2Fs can bind their cognate DNA elements, in cooperation with DP1, and the associated Rb proteins then mediate repression. However, p130, while binding E2F4 but independent of an E2F-binding DNA element, associates with the MuvB-complex, replacing B-Myb. MuvB binds the CHR element of DNA. As a consequence of E2F4 and p130 being tethered to the CHR, the promoter is repressed. The first two mechanisms were reported earlier, …