Ubiquitination in DNA damage signaling – structure of the Mms2/Ubc13 ubiquitin conjugating enzyme

Part of the response to DNA double strand breaks is the accumulation of a novel form of polyubiquitin modification on chromatin near the double strand break. This ubiquitination is dependent upon MDC1 and the novel ubiquitin conjugating enzyme, Mms2/Ubc13. We determined the structure of the Mms2/Ubc13 complex, revealing a novel heterodimeric E2 complex that facilitates the alignment of ubiquitins to generate chains in which one ubiquitin is linked to its neighbor via an isopeptide bond between Lys63 and the C-terminus of the next ubiquitin in the chain. Unlike ubiquitin chains involving Lys48 linkages, modification by Lys63 chains does not target the tagged protein for degradation, but instead is recognized by specialized binding proteins such as RAP80 and RAD18.

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Huang, J., Huen, M. S. Y., Kim, H., Leung, C. C. Y., Glover, J. N. M., Yu, X. and Chen, J. (2009) RAD18 transmits DNA damage signaling to elicit homologous recombination repair. Nature Cell Biology 11(5):592-603.
Pelzer, L., Pastushok, L., Moraes, T., Glover, J. N., Ellison, M. J., Ziola, B. and Xiao, W. (2009) Biological significance of structural differences between two highly conserved Ubc variants. Biochem. Biophys. Res. Commun. 378(3):563-568. PDF
Hamilton, K. S., Ellison, M. J., Barber, K. R., Williams, R. S., Huzil, J. T., McKenna, S., Ptak, C., Glover, M. and Shaw, G. S. (2001) Structure of a conjugating enzyme-ubiquitin thiolester intermediate reveals a novel role for the ubiquitin tail. Structure 9:897-904.
Moraes, T. F., Edwards, R. A., McKenna, S., Pastushok, L., Xiao, W., Glover, J. N. M. and Ellison, M. J. (2001) Crystal structure of the human ubiquitin conjugating enzyme complex, hMms2-hUbc13. Nature Structure Biology 8:669-673. PDF