Meta-Biol

• Pathways

Apoptotic transcriptional targets of TP53 include genes that regulate the permeability of the mitochondrial membrane and/or cytochrome C release, such as BAX, BID, PMAIP1 (NOXA), BBC3 (PUMA) and probably BNIP3L, AIFM2, STEAP3, TRIAP1 and TP53AIP1 (Miyashita and Reed 1995, Oda et al. 2000, Samuels-Lev et al. 2001, Nakano and Vousden 2001, Sax et al. 2002, Passer et al. 2003, Bergamaschi et al. 2004, Li et al. 2004, Fei et al. 2004, Wu et al. 2004, Park and Nakamura 2005, Patel et al. 2008, Wang et al. 2012, Wilson et al. 2013), thus promoting the activation of the apoptotic pathway.

Transcriptional activation of TP53AIP1 requires phosphorylation of TP53 at serine residue S46 (Oda et al. 2000, Taira et al. 2007). Phosphorylation of TP53 at S46 is regulated by another TP53 pro-apoptotic target, TP53INP1 (Okamura et al. 2001, Tomasini et al. 2003).

RNA polymerase II (Pol II) is the central enzyme that catalyses DNA- directed mRNA synthesis during the transcription of protein-coding genes. Pol II consists of a 10-subunit catalytic core, which alone is capable of elongating the RNA transcript, and a complex of two subunits, Rpb4/7, that is required for transcription initiation.
The transcription cycle is divided in three major phases: initiation, elongation, and termination. Transcription initiation include promoter DNA binding, DNA melting, and initial synthesis of short RNA transcripts. The transition from initiation to elongation, is referred to as promoter escape and leads to a stable elongation complex that is characterized by an open DNA region or transcription bubble. The bubble contains the DNA-RNA hybrid, a heteroduplex of eight to nine base pairs. The growing 3-end of the RNA is engaged with the polymerase complex active site. Ultimately transcription terminates and Pol II dissocitates from the template.

Gene expression encompasses transcription and translation and the regulation of these processes. RNA Polymerase I Transcription produces the large preribosomal RNA transcript (45S pre-rRNA) that is processed to yield 18S rRNA, 28S rRNA, and 5.8S rRNA, accounting for about half the RNA in a cell. RNA Polymerase II transcription produces messenger RNAs (mRNA) as well as a subset of non-coding RNAs including many small nucleolar RNAs (snRNA) and microRNAs (miRNA). RNA Polymerase III Transcription produces transfer RNAs (tRNA), 5S RNA, 7SL RNA, and U6 snRNA. Transcription from mitochondrial promoters is performed by the mitochondrial RNA polymerase, POLRMT, to yield long transcripts from each DNA strand that are processed to yield 12S rRNA, 16S rRNA, tRNAs, and a few RNAs encoding components of the electron transport chain. Regulation of gene expression can be divided into epigenetic regulation, transcriptional regulation, and post-transcription regulation (comprising translational efficiency and RNA stability). Epigenetic regulation of gene expression is the result of heritable chemical modifications to DNA and DNA-binding proteins such as histones. Epigenetic changes result in altered chromatin complexes that influence transcription. Gene Silencing by RNA mostly occurs post-transcriptionally but can also affect transcription. Small RNAs originating from the genome (miRNAs) or from exogenous RNA (siRNAs) are processed and transferred to the RNA-induced silencing complex (RISC), which interacts with complementary RNA to cause cleavage, translational inhibition, or transcriptional inhibition.