The proper regulation of apoptosis is essential for the survival of multicellular organisms. It has become clear that the post-translational modification of apoptotic proteins by ubiquitination regulates key components in cell death signaling cascades. Ubiquitination, which describes the covalent modification of target proteins with ubiquitin, has a profound bearing on the fate and function of its substrates and requires the enzymic activity of an E1, an E2 and an E3 protein (of which many subtypes are known to date). While ubiquitination, similarly to phosphorylation, is a reversible modification, in mammals, approximately 100 DUBs (EC 3.4.19.12) function to depolymerize and remove ubiquitin adducts as well.
Human ubiquitin-specific protease 1 (USP1), which is associated with UAF1, has been identified as the deubiquitinase (DUB) responsible for deubiquitinating PCNA, FANCD2 and FANCI in the DNA damage response. USP1 is also required for the FANCD2 foci formation in both mouse and human cells. A high level of genomic instability has been linked to deficiency in human ATAD5 (the human ortholog of yeast Elg1), which mediates PCNA deubiquitination by USP1-UAF1. Together, these observations suggest that the DUB activity of USP1-UAF1 is important for the normal cellular response to DNA damage[1]. USP7 and USP47 are two other examples of deubiquitination enzymes that assist in the highly complex processes that regulate apoptosis[2]. USP7 (or HAUSP) is most popularly known as a direct antagonist of Mdm2, the E3 ubiquitin ligase for the p53 tumor suppressor protein[3]. Similarly, USP47 was recently identified as a novel interactor of the E3 ubiquitin ligase SCFβ-Trcp. However, in contrast with the effects of USP7, USP47 depletion seems not to depend on p53 status[4].
USP2 is a deubiquitinating enzyme (DUB) that removes ubiquitin thereby stabilizing a range of substrates, including MDM2 (a regulator of p53), fatty-acid synthase, cyclin D1, and proteins important for the circadian rhythm, such as CRY1. Moreover, USP2 is up-regulated in various cancers.[5]