270
R. E. HARRINGTON et al.
level and phosphorylation state. In the present model, the C-termini interacting
electrostatically with the DNA can increase the bend simply by pulling the DNA
toward the center of the bend. This is of special interest since the C-termini
undergo post-translational modifications including acetylation, phosphorylation
and dephosphorylation, apparently initiated by DNA damage (Sakaguchi et ai.,
1998; Kapoor et al., 1998; Lu et al., 1998; Waterman et ai., 1998).
The structural model also offers insights into the remarkable binding specificity and selectivity of p53. The range of p53 function is so broad, including that of
pleiotropic transcription factor and enhancer, that the demands for binding specificity and selectivity are necessarily extraordinary. This is likely accomplished
through its tetrameric association with a repetitive binding site in which precise
steric fit is extremely important. Steric fit is accommodated through both DNA
bending and twisting which are evidently tightly coupled as discussed above.
Therefore, it becomes possible for binding specificity in the p53 system to be regulated by local supercoiling in promoter regions (Liu and Wang, 1987) as well as
by specific bending in larger transcriptional complexes or by nearby architectural elements (Jayaraman et al., 1998).
4
Acknowledgements
The authors are grateful to Dr. Carl W. Anderson and Dr. Wilma K. Olson for
valuable discussions. The work was supported by research grants CA70274 and
GM53517 from the National Institutes of Health (REH).
References
Anderson, M.E., Woelker, B., Reed, M., Wang, P. and Tegtmeyer, P. (1997) Mol. Cell. BioI., 17,
6255-6264.
Appella, E. and Anderson, C.W. (1994) Biochim. Italia, 1, 19-28.
Appella, E., Nagaich, A.K., Zhurkin, V.B. and Harrington, R.E. (1998) J. Prot. Chem., 17,527-528.
Arrowsmith, C.H. and Morin, P. (1996) Oncogene, 12, 1379-1385.
Balagurumoorthy, P., Sakamoto, H., Lewis, M.S., Zambrano, N., Clore, G.M., Gronenborn, A.M.,
Appella, E. and Harrington, R.E. (1995). Proc. Natl. Acad Sci. USA, 92, 8591-8595.
Baudier, J., Delphin, c., Grunwald, D., Khochbin, S. and Lawrence, J.J., Proc. Natl. Acad. Sci. USA, 89,
11627-11631
Bewley, C.A., Gronenborn, A.M. and Clore, G.M. (1998) Annu. Rev. Biophys. Biomol. Struct., 27,
105-131.
Bishoff, J.R., Friedman, P.N., Marshak, D.R., Prives, C. and Beach, D. (1990) Proc. Nat!. Acad. Sci. USA,
87,4766-4770
Chen, X.B., Farmer, G., Zhu, H., Prywes, R. and Prives, C. (1993) Genes Develop., 7,1837-1849.
Cho, Y.J., Gorina, S., Jeffrey, P.D. and Pavletich, N.P. (1994) Science, 265, 346-355.
Cook, J.L., Re, R., Giardina, J.F., Fontenot, F.E., Cheng, D.Y. and Alam, J. (1995) Oncogene, 11,
723-733.
Deleo, A.B., Jay, G., Appella, E., DuBois, G.C., Law, L.w. and Old, L.J. (1979) Proc. Natl. Acad. Sci. USA,
76, 2420-2424.
Dickerson, R.E. (1998) Nucleic Acids Res., 26,1906-1926.
Durell, S.R., Appella, E., Nagaich, A.K., Harrington, R.E., Jernigan, R.L. and Zhurkin, V.B. (1998) In
Sarma, R.H. and Sarma, M.H. (eds.), Structure, Motion, Interaction and Expression of Biological
Macromolecules. Proceedings of the Tenth Conversation. Adenine Press, Schenectady, NY, 2,
277-295.
EI-Deiry, W.S., Kern, S.E., Pietenpol, J.A., Kinzler, K.W. and Vogelstein, B. (1992) Nature Genetics, 1,
45-49.
R. E. HARRINGTON et al.
level and phosphorylation state. In the present model, the C-termini interacting
electrostatically with the DNA can increase the bend simply by pulling the DNA
toward the center of the bend. This is of special interest since the C-termini
undergo post-translational modifications including acetylation, phosphorylation
and dephosphorylation, apparently initiated by DNA damage (Sakaguchi et ai.,
1998; Kapoor et al., 1998; Lu et al., 1998; Waterman et ai., 1998).
The structural model also offers insights into the remarkable binding specificity and selectivity of p53. The range of p53 function is so broad, including that of
pleiotropic transcription factor and enhancer, that the demands for binding specificity and selectivity are necessarily extraordinary. This is likely accomplished
through its tetrameric association with a repetitive binding site in which precise
steric fit is extremely important. Steric fit is accommodated through both DNA
bending and twisting which are evidently tightly coupled as discussed above.
Therefore, it becomes possible for binding specificity in the p53 system to be regulated by local supercoiling in promoter regions (Liu and Wang, 1987) as well as
by specific bending in larger transcriptional complexes or by nearby architectural elements (Jayaraman et al., 1998).
4
Acknowledgements
The authors are grateful to Dr. Carl W. Anderson and Dr. Wilma K. Olson for
valuable discussions. The work was supported by research grants CA70274 and
GM53517 from the National Institutes of Health (REH).
References
Anderson, M.E., Woelker, B., Reed, M., Wang, P. and Tegtmeyer, P. (1997) Mol. Cell. BioI., 17,
6255-6264.
Appella, E. and Anderson, C.W. (1994) Biochim. Italia, 1, 19-28.
Appella, E., Nagaich, A.K., Zhurkin, V.B. and Harrington, R.E. (1998) J. Prot. Chem., 17,527-528.
Arrowsmith, C.H. and Morin, P. (1996) Oncogene, 12, 1379-1385.
Balagurumoorthy, P., Sakamoto, H., Lewis, M.S., Zambrano, N., Clore, G.M., Gronenborn, A.M.,
Appella, E. and Harrington, R.E. (1995). Proc. Natl. Acad Sci. USA, 92, 8591-8595.
Baudier, J., Delphin, c., Grunwald, D., Khochbin, S. and Lawrence, J.J., Proc. Natl. Acad. Sci. USA, 89,
11627-11631
Bewley, C.A., Gronenborn, A.M. and Clore, G.M. (1998) Annu. Rev. Biophys. Biomol. Struct., 27,
105-131.
Bishoff, J.R., Friedman, P.N., Marshak, D.R., Prives, C. and Beach, D. (1990) Proc. Nat!. Acad. Sci. USA,
87,4766-4770
Chen, X.B., Farmer, G., Zhu, H., Prywes, R. and Prives, C. (1993) Genes Develop., 7,1837-1849.
Cho, Y.J., Gorina, S., Jeffrey, P.D. and Pavletich, N.P. (1994) Science, 265, 346-355.
Cook, J.L., Re, R., Giardina, J.F., Fontenot, F.E., Cheng, D.Y. and Alam, J. (1995) Oncogene, 11,
723-733.
Deleo, A.B., Jay, G., Appella, E., DuBois, G.C., Law, L.w. and Old, L.J. (1979) Proc. Natl. Acad. Sci. USA,
76, 2420-2424.
Dickerson, R.E. (1998) Nucleic Acids Res., 26,1906-1926.
Durell, S.R., Appella, E., Nagaich, A.K., Harrington, R.E., Jernigan, R.L. and Zhurkin, V.B. (1998) In
Sarma, R.H. and Sarma, M.H. (eds.), Structure, Motion, Interaction and Expression of Biological
Macromolecules. Proceedings of the Tenth Conversation. Adenine Press, Schenectady, NY, 2,
277-295.
EI-Deiry, W.S., Kern, S.E., Pietenpol, J.A., Kinzler, K.W. and Vogelstein, B. (1992) Nature Genetics, 1,
45-49.