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the substrates by ubiquitin-specific proteases (USPs) or deubiquitinating
enzymes. 45 In contrast to the lysine 48-linked modification, polyubiquitin
chains consisting of lysine 63 linkages are considered as nondegradative sig-
nals for recruiting and activating kinases. 46 Ubiquitination was discovered
and characterized in the context of nonlysosomal protein degradation by
the 26S proteasomes. However, it has turned out to be a highly versatile pro-
tein modification because it can alter the protein three-dimensional struc-
ture, leading to changes in protein location and/or activity, thereby
regulating a wide array of biological processes, including cell-cycle control,
DNA repair, stress response, transcription, gene silencing, protein
processing, apoptosis, endocytosis, and signal transduction.
1.3. Deubiquitination
Generally, biochemical pathways are reversible such that there are “on” and
“off” cycles; this reversibility is critical for the regulation of biological and
physiological outcomes. Substrate ubiquitination is an excellent example
of such regulation because it is a dynamic and reversible modification.
Ubiquitinated proteins are deubiquitinated by specific proteases known as
deubiquitinases (DUBs) or USPs that cleave the iso-peptide bond between
carboxyl terminus of ubiquitin and the amino group of the substrate. Bio-
informatic analyses have identified that the human genome encodes 100
putative DUBs, of which 79 are postulated to be functional. The DUBs have
been divided into five distinct classes based on sequence and structural
homology. 47 Four of the five classes identified to date are cysteine proteases
with a classical papain active catalytic site structure encompassing the cata-
lytic triad of cysteine, histidine, and a third residue consisting of aspartic acid,
asparagine, or rarely, serine. These four classes are (1) ubiquitin carboxy-
terminal hydrolases (4 members), (2) USPs (over 58 members), (3)
Machado-Joseph Domain (5 members), and (4) the ovarian tumor-related
family (14 members). The fifth class, called jab1/MPN domain-associated
metalloisopeptidase motif DUBs, is composed of Zn 2 þ -containing meta-
lloproteases (14 members). Studies have demonstrated that DUBs play an
important role in several aspects of the ubiquitin-proteasome system, and
mutations in DUBs have been implicated in a number of diseases, ranging
from hereditary cancer to neurodegeneration. The abundance of DUB
family members suggests diversity and specificity of DUB activity, although
currently our knowledge about the physiological substrates of individual
members of the DUB family is limited.
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