The dual role model for p53 in maintaining genomic integrity

Abstract

The tumour suppressor p53 is a potent mediator of cellular responses against genotoxic insults. In this review we describe the multiple functions of p53 in response to DNA damage, with an emphasis on p53's role in DNA repair. We summarize data demonstrating that p53 actively participates in various processes of DNA repair and DNA recombination via its ability to interact with components of the repair and recombination machinery, and by its various biochemical activities. An important aspect in evaluating p53 functions is provided by the finding that the core domain of p53 harbours two mutually exclusive biochemical activities, sequence-specific DNA binding required for its transactivation function, and 3'-5' exonuclease activity, possibly involved in aspects of DNA repair. Based on the finding that modifications of p53 which lead to activation of its sequence-specific DNA-binding activity result in inactivation of its 3'-5' exonuclease activity, we propose that p53 exerts its functions as a 'guardian of the genome' at various levels: in its noninduced state, p53 should not be regarded as a 'dead' protein but, for example, via its exonuclease activity might be actively involved in prevention and repair of endogenous DNA damage. Upon induction through exogenous DNA damage, p53 will exert its well-documented functions as a superior response element in various types of cellular stress. This dual role model for p53 in maintaining genomic integrity significantly enhances p53's possibilities as a guardian of the genome.

Dissociation of p53-mediated suppression of homologous recombination from G1/S cell cycle checkpoint control

“…Deppert and colleagues (Janus et al, 1999b) recently made the intriguing observation that p53's exonuclease and sequencespeci®c DNA binding activities appeared to be mutually exclusive functions. This has led the authors to formulate a dual p53 model which may signi®cantly extend p53's role as a guardian of the genome (Janus et al, 1999a), and which is supported by our data: In addition to the well documented cellular stress responses mediated by activated p53, the model postulates regulatory functions in DNA metabolism such as repair of endogenous DNA damage, control of replication and recombination when p53 is in its latent' state which is generally considered inactive for transcriptional regulation. To test this hypothesis more directly, it will be necessary to de®ne this latent protein form in more detail, for example by transfecting a combination of trans-activation and phosphorylation defective candidate mutants into a p53-null cellular background, and by subsequent study of recombinational endpoints in vitro and in vivo.…”

“…The data presented here imply that p53 can maintain genome integrity by suppression of spontaneous HR independently of the G1/S checkpoint and probably also in the absence of transcriptional activation. Furthermore, p53 has been suggested to act in a post-replicative mismatch repair pathway (Mummenbrauer et al, 1996;Huang, 1998), it co-localizes with DNA synthesis and the DNA replication apparatus (Huang, 1998), interacts with viral replication (Deppert, 1994), migrates into the nucleus with S phase (Shaulsky et al, 1990;Martinez et al, 1991), and interacts with a variety of proteins involved in DNA repair (for further review, see Janus et al, 1999a). Deppert and colleagues (Janus et al, 1999b) recently made the intriguing observation that p53's exonuclease and sequencespeci®c DNA binding activities appeared to be mutually exclusive functions.…”

“…In certain cell types and situations, p53 can alternatively trigger apoptosis (Ko and Prives, 1996;Sherr, 1996). p53 has also been reported to be involved in control of the G2/M checkpoint and a variety of other aspects of cell proliferation and DNA metabolism (Ko and Prives, 1996;Levine, 1997;Janus et al, 1999a). Suppression of spontaneous homologous recombination (HR) has recently been established as a new endpoint of wild-type p53 function (Meyn et al, 1994;Xia et al, 1994;WiesmuÈ ller et al, 1996;Bertrand et al, 1997;Mekeel et al, 1997;DuddenhoÈ er et al, 1998).…”

Absence of acute apoptotic response to genotoxic carcinogens in p53‐deficient mice is associated with increased susceptibility to azoxymethane‐induced colon tumours

“…Some consider that the apoptotic response to carcinogen follows when there is a failure of DNA repair mechanisms associated with cell cycle arrest and subsequent entry of the cell into the S phase, where the adduct is recognised and triggers apoptosis. [30][31][32] Indeed, apoptosis reaches maximum within 6-8 hr, 12 which seems too rapid for it to be dependent on cells entering S phase. Indeed, one study has shown that apoptosis precedes activation of DNA repair enzymes such as MGMT, 9 pointing to AARGC being a primary mechanism for controlling excessive mutational load resulting from carcinogens.…”

Role of heteroduplex joints in the functional interactions between human Rad51 and wild-type p53

“…p53 is known to accumulate and to become activated in response to DNA damage in order to exert its functions as a cell cycle regulatory protein via its transcriptional activities (reviewed in Lane, 1992;Vogelstein and Kinzler, 1993). Accumulating evidence suggests that activities of p53 in DNA repair contribute to its functions in genome stabilization (reviewed in Janus et al, 1999a). Several studies pointed towards a role of p53 in nucleotide excision repair possibly via interactions with the helicase subunits of the dual transcription/nucleotide excision repair factor TFIIH (Smith et al, 1995;Wang et al, 1995;Leveillard et al, 1996;Mirzayans et al, 1996;Ford and Hanawalt, 1997) or indirectly by suppressing a recombinational repair bypass mechanism (Ishizaki et al, 1994;Cleaver et al, 1999).…”