REGULATION OF P53 DNA BINDING

p53 is one of the most frequently mutated genes in human cancers and, as a result, is also one of the most well-studied genes in the history of cancer research. Although many functions have been ascribed to p53 over the years, one of the first activities to be characterized was the ability to bind DNA sequence-specifically through its central domain (reviewed in Vogelstein & Kinzler, 1992). This domain, also frequently referred to as “the core” due to its protease resistance (Bargonetti et al., 1993; Pavletich et al., 1993), contains the most evolutionarily conserved sequences of the protein, both between p53 proteins from different species and between the different p53 family members, p63 and p73 (reviewed in Yang et al., 2002). This region is also the most frequently mutated domain of p53 in the major forms of human cancer (Hainaut & Hollstein, 2000; Olivier et al., 2002). Consequently much research has focused on understanding this crucial ability as well as its regulation. Indeed, the regulation of p53 DNA binding has generated much debate recently, specifically with regard to the role of the C-terminus. In addition to a sequence-specific DNA binding domain, p53 also contains a transactivation domain in its N-terminus and can therefore bind and transactivate targets in vivo and in vitro (reviewed in Vogelstein & Kinzler, 1992). Other well-characterized functional domains are diagrammed in Figure 1. This chapter will focus on what is known about the involvement and regulation of the individual domains of p53 in sequence-specific DNA binding.