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Specific binding of MAR/SAR DNA-elements by mutant p53
B F Müller1, D Paulsen, W Deppert
1Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie, Hamburg, Germany.
Abstract:
Inactivation of the tumor suppressor p53 by single missense point mutations characterizes a large number of human tumors. At least some mutant p53 proteins not only have lost the tumor suppressor function, but at the same time reveal a variety of dominant oncogenic properties. The molecular basis of this 'gain of function' is still unknown. In this report we describe a new biochemical activity of mutant p53, the specific high-affinity interaction with MAR/SAR DNA-elements (nuclear matrix/scaffold attachment regions). This DNA-binding activity can be distinguished from the previously reported DNA-binding activities of p53 by its specificity for mutant p53, the high binding affinity, and the domains of the mutant p53 molecule involved in MAR/SAR DNA-binding. The MAR/SAR-binding region of mutant p53 maps to a bipartite domain consisting of the mutated core region and the C-terminal 60 amino acids, carrying the unspecific DNA-binding domain and the oligomerization motif. MAR/SAR elements are considered as important regulatory elements in a variety of nuclear processes. We propose a model according to which the specific interaction of mutant p53 with MAR/SAR elements might interfere with these processes, thereby exerting pleiotropic oncogenic effects.
Insights
Mutant p53 proteins gain oncogenic properties by interacting with specific DNA elements. This novel interaction with nuclear matrix/scaffold attachment regions (MAR/SAR) may drive cancer progression.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Single missense point mutations inactivate the tumor suppressor p53 in many human cancers.
- Mutant p53 proteins can acquire dominant oncogenic 'gain of function' properties.
- The molecular mechanisms underlying mutant p53's oncogenic functions remain largely unknown.
Purpose of the Study:
- To identify novel biochemical activities of mutant p53.
- To elucidate the molecular basis of mutant p53's oncogenic 'gain of function'.
Main Methods:
- Biochemical assays to detect specific DNA-binding activities of mutant p53.
- Characterization of the binding affinity and specificity for MAR/SAR DNA elements.
- Mapping of the MAR/SAR-binding region within mutant p53.
Main Results:
- Mutant p53 exhibits a specific, high-affinity interaction with MAR/SAR DNA elements.
- This DNA-binding activity is distinct from previously identified p53 DNA-binding activities.
- The MAR/SAR-binding region involves the mutated core and C-terminal domains of mutant p53.
Conclusions:
- Mutant p53 possesses a novel biochemical activity involving MAR/SAR DNA elements.
- This specific interaction may contribute to the oncogenic properties of mutant p53.
- Interference with nuclear processes regulated by MAR/SAR elements could mediate pleiotropic oncogenic effects.