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Studying Response Element Specificity in the Transcription Factor p73 by Molecular Dynamics


p73 is responsible for the regulation of many of the cell's critical life processes along with the entire p53- family. Additionally, due to its transcriptional cross- over present among the p53-family members, great promise is held for p73 to substitute for the tumor suppression function absent in mutant-p53, which is present in 50 % of all cancers. Critically important for the regulation of transcription is the response element (RE) sequence recognition by the p53-family. Although some is known about how the response element affects the level of transcription, little is understood, in particular concerning the mechanism for how transcription is regulated for p53-family genes. In this work, molecular dynamics (MD) is used to study the recognition of the response element flanking-site by the p73-DBD dimer. In particular, two response elements sequences are examined: an apoptotically relevant, guanine-rich RE, and a cell cycle arrest/DNA repair relevant, adenine-rich RE. The results highlight a conformational change of the p73-DBD/ RE complex as a result of the guanine-rich sequences, suggesting a distinct mechanism of transcription regulation in relation to RE's that lack a guanine-rich flanking-site. In addition, simulations showed conformational states of a partially unbound p73-DBD/RE complex that serve to propose a model for p73 recognition of nonspecific DNA and REs

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