The ability of ubiquitin to regulate myriad cellular activities results, in part, from its unique capacity to be linked into chains. Chains assembled through ubiquitin's lysine 48 residue target substrates to the proteasome for degradation, but chains can also be assembled through ubiquitin's six other lysine residues.' Of these noncanonical (i.e. non-K48-linked) chains, functions have only been ascribed to those assembled through lysine 63. In a non-proteolytic manner, K63-linked chains modulate both the UV-induced DNA damage response and NF-kB signaling, two cellular pathways important in the progression of certain cancers and inflammatory diseases, However, the molecular details by which these noncanonical polyubiquitin chains fulfill their functions are poorly understood. The focus of this proposal is on using biochemical and proteomic approaches to determine how cells utilize noncanonical polyubiquitin chains as regulated signaling elements. Specifically, the goal is to establish a paradigm for how these chains are recognized, what factors bind to them, and how such signals are ultimately turned off.
| Cooper, Eric M; Boeke, Jef D; Cohen, Robert E (2010) Specificity of the BRISC deubiquitinating enzyme is not due to selective binding to Lys63-linked polyubiquitin. J Biol Chem 285:10344-52 |
| Cooper, Eric M; Cutcliffe, Colleen; Kristiansen, Troels Z et al. (2009) K63-specific deubiquitination by two JAMM/MPN+ complexes: BRISC-associated Brcc36 and proteasomal Poh1. EMBO J 28:621-31 |
| Wang, Tao; Yin, Luming; Cooper, Eric M et al. (2009) Evidence for bidentate substrate binding as the basis for the K48 linkage specificity of otubain 1. J Mol Biol 386:1011-23 |
