The dual role model for p53 in maintaining genomic integrity

被引:121
作者
Janus, F
Albrechtsen, N
Dornreiter, I
Wiesmüller, L
Grosse, F
Deppert, W
机构
[1] Univ Hamburg, Heinrich Pette Inst Expt Virol & Immunol, D-20251 Hamburg, Germany
[2] Inst Mol Biotechnol, D-07745 Jena, Germany
关键词
p53; DNA repair; DNA damage; DNA recombination; DNA replication; sequence-specific DNA binding; 3 '-5 ' exonuclease;
D O I
10.1007/s000180050266
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:12 / 27
页数:16
相关论文
共 177 条
[1]   Interaction between replication protein A and p53 is disrupted after UV damage in a DNA repair-dependent manner [J].
Abramova, NA ;
Russell, J ;
Botchan, M ;
Li, R .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (14) :7186-7191
[2]   MAT1, cdk7 and cyclin H form a kinase complex which is UV light-sensitive upon association with TFIIH [J].
Adamczewski, JP ;
Rossignol, M ;
Tassan, JP ;
Nigg, EA ;
Moncollin, V ;
Egly, JM .
EMBO JOURNAL, 1996, 15 (08) :1877-1884
[3]  
Adams PD, 1996, MOL CELL BIOL, V16, P6623
[4]   P53 CONTROLS BOTH THE G(2)/M AND THE G(1) CELL-CYCLE CHECKPOINTS AND MEDIATES REVERSIBLE GROWTH ARREST IN HUMAN FIBROBLASTS [J].
AGARWAL, ML ;
AGARWAL, A ;
TAYLOR, WR ;
STARK, GR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (18) :8493-8497
[5]   POSTTRANSLATIONALLY MODIFIED 14-3-3-ISOFORMS AND INHIBITION OF PROTEIN-KINASE-C [J].
AITKEN, A ;
HOWELL, S ;
JONES, D ;
MADRAZO, J ;
MARTIN, H ;
PATEL, Y ;
ROBINSON, K .
MOLECULAR AND CELLULAR BIOCHEMISTRY, 1995, 149 :41-49
[6]   THE ROLE OF SPECIFIC ISOFORMS OF 14-3-3 PROTEIN IN REGULATING PROTEIN-KINASE ACTIVITY IN THE BRAIN [J].
AITKEN, A ;
AMESS, B ;
HOWELL, S ;
JONES, D ;
MARTIN, H ;
PATEL, Y ;
ROBINSON, K ;
TOKER, A .
BIOCHEMICAL SOCIETY TRANSACTIONS, 1992, 20 (03) :607-611
[7]  
ALANI E, 1997, J MOL BIOL, V265
[8]   ACCUMULATION OF WILD-TYPE P53 PROTEIN UPON GAMMA-IRRADIATION INDUCES A G(2) ARREST-DEPENDENT IMMUNOGLOBULIN-KAPPA LIGHT-CHAIN GENE-EXPRESSION [J].
ALONIGRINSTEIN, R ;
SCHWARTZ, D ;
ROTTER, V .
EMBO JOURNAL, 1995, 14 (07) :1392-1401
[9]  
ASHLEY T, 1995, CHROMOSOMA, V104, P19, DOI 10.1007/BF00352222
[10]   P53 BINDS SINGLE-STRANDED-DNA ENDS THROUGH THE C-TERMINAL DOMAIN AND INTERNAL DNA SEGMENTS VIA THE MIDDLE DOMAIN [J].
BAKALKIN, G ;
SELIVANOVA, G ;
YAKOVLEVA, T ;
KISELEVA, E ;
KASHUBA, E ;
MAGNUSSON, KP ;
SZEKELY, L ;
KLEIN, G ;
TERENIUS, L ;
WIMAN, KG .
NUCLEIC ACIDS RESEARCH, 1995, 23 (03) :362-369