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

  • Author(s): Murano, George Anthony
  • et al.
Abstract

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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