(DSBs). The cells possess a robust response mechanism to DNA lesions, which triggers a range of signals to adequately handle the damage and maintain genomic integrity, collectively known as the DNA damage response (DDR). Central to mediating the response are the DDR kinases - ataxia telangiectasia-mutated (ATM), ATM and RAD3-related (ATR) and DNA-dependent protein kinase (DNA-PKcs). Of these, ATM plays a pivotal role - its signaling is activated by DSBs to promote the double-strand repair and prompt cell cycle checkpoint pathways, regulate cell fate decision (apoptosis or senescence), transcription and metabolic pathways. Of these, some are mediated by activation of p53 signaling. Distinct types of stress and/or damage summon distinct detection and/or repair proteins which in turn, via post-translational modifications and protein-protein interactions, relay the message to p53. The result is increased stabilization and reduced repression of p53, enhanced sequence specific DNA binding and regulation of transcription of many target genes. It is believed that hundreds of RNA polymerase II-transcribed genes are directly regulated by p53 and possibly thousands, indirectly. p53 consists of several domains - the N-terminal transactivation domain (TAD) with the two subdomains TAD-I (residues 20-40 - click to see the structure of a TAD-I fragment in complex with MDM2 from Xenopus Laevis) and Tad-II (residues 40-60, a proline rich domain (residues 63-97) the evolutionary conserved DNA-binding domain (DBD - click to see the DBD in complex with DNA ) (residues 100-300), a linker region ( residues 301-323) a tetramerization domain (tet - click to see the tet domain ) (residues 324-355) and the basic carboxy-terminus domain (CTD) (residues 360-393). In the unstressed state, Mdm2 binds to and sterically blocks the transactivation domain of p53, it also acts as an E3 ubiquitin ligase for p53 and itself. Mdm2 is a target of p53, hence the negative feedback loop it provides. The structurally related Mdm4 (Mdmx) also negatively regulates p53. Stresses disrupt the p53-Mdm2 interaction, stabilize p53 or destabilize Mdm2. Once stabilized, p53 translocates to the nucleus where it binds to its response elements (RE) as a tetramer (dimer of dimers). Binding to DNA is dependent on the ability of DBD to co-ordinate a Zn++ ion through several cysteine residues. DNA binding also results in structural changes as evidenced in bending of DNA. Once bound, p53 recruits histone modifying enzymes, of which the acetyltransferases are best documented. The subsequent loosening of chromatin structure allows for the assembly of transcriptional machinery and initiation of RNA polymerase II transcription of target genes (p53 may also play a role in the elongation phase of RNA polII transcription). In contrast, p53 may inhibit transcription from RNA polymerase I and III (not shown). p53 is the target of numerous modifications that modulate its activity (see p53 regulators) and for many interacting partners via its domains (see p53 interacting partners). Target genes are regulated in a context-, locus- and stimulus-specific manner, with Tp53 being both an activator and also a repressor (see p53 targets). Tp53 can repress gene expression directly or indirectly via sequestration of other transcription factors or via non-coding RNA targets (see p53 targets). Many microRNAs (miRNAs) have been reported as targets of which some provide p53 regulatory feedback or further its function. In addition, evidence is emerging for the role of long non-coding RNA (lncRNAs) as both regulators and effectors of p53 (see non-coding RNA, p53 targets, regulators, effectors). It is well known that p53 is mutated in many types of cancer with over 50% of tumors exhibiting variation at this locus. Many mutations 'cluster' within the DBD domain and many result in a pro-oncogenic protein. In addition, tumors also exhibit amplification of both Mdm2 and Mdm4 genes; the two genes are reported to also have p53 independent functions. To see the ontology report for annotations, GViewer and download, click here [click to see associated KEGG map 04115]...(less)