Ubiquitin (191339) is a highly conserved 76-amino acid protein involved in the regulation of intracellular protein breakdown, cell cycle regulation, and stress response. Ubiquitin is released from degraded proteins by disassembly of the polyubiquitin chains, which is mediated by ubiquitin-specific proteases (USPs) (see USP1; 603478).

By screening HeLa and Jurkat cDNA libraries with a monoclonal antibody against mitotic phosphoproteins, Cai et al. (1999) identified a cDNA encoding USP16, which they called UBPM. The 823-amino acid USP16 protein shares sequence similarities with other USPs and was shown to cleave standard substrates in vitro. Northern blot analysis detected a 3-kb transcript in all tissues tested. Using Western blot analysis, Cai et al. (1999) determined that USP16 is maximally phosphorylated before metaphase and dephosphorylated in anaphase. Immunofluorescence microscopy showed that USP16 localizes to the cytoplasm and is expressed diffusely during mitosis. SDS-PAGE analysis indicated that USP16 hydrolyzes histones H2A (see 613499) and H2B (see 609904), the major ubiquitinated proteins of chromatin.

Joo et al. (2007) reported the identification and functional characterization of the major deubiquitinase for histone H2A, UbpM (also called USP16). USP16 preferred nucleosomal substrates in vitro, and specifically deubiquitinated histone H2A but not H2B in vitro and in vivo. Notably, knockdown of USP16 in HeLa cells resulted in slow cell growth rates owing to defects in the mitotic phase of the cell cycle. Further studies revealed that H2A deubiquitination by USP16 is a prerequisite for subsequent phosphorylation of ser10 of H3 (see 602810) and chromosome segregation when cells enter mitosis. Furthermore, Joo et al. (2007) demonstrated that USP16 regulates Hox gene (see 142950) expression through H2A deubiquitination and that blocking the function of USP16 results in defective posterior development in Xenopus laevis. Joo et al. (2007) concluded that their study identified the major deubiquitinase for histone H2A and demonstrated that H2A deubiquitination is critically involved in cell cycle progression and gene expression.

Romanoski et al. (2010) reported genetic analysis of thousands of transcript abundance traits in human primary endothelial cell (EC) lines in response to proinflammatory oxidized phospholipids implicated in cardiovascular disease. Of the 59 most regulated transcripts, approximately one-third showed evidence of gene-by-environment (GxE) interaction. The interactions resulted primarily from effects of distal, trans-acting loci. Whereas most GxEQTL were associated to 1 expression trait (gene expression value) only, a locus on chromosome 21 represented by rs2831649 was associated to the oxidized phospholipid response of 7 distal expression traits. Oxidized phospholipid-treated expression levels of USP16 showed evidence (p = 3.3 x 10(-5)) of local expression association to rs2831649. The G allele of rs2831649 was associated with higher USP16 expression as well as greater oxidized phospholipid-induced expression of target genes. Romanoski et al. (2010) hypothesized that USP16 regulated oxidized phospholipid responsiveness for the 7 highly induced genes associated to rs2831649 identified in the distal analysis: ASNS (108370), CEBPB (189965), SLC7A11 (607933), SLC7A5 (600182), SLC3A2 (158070), TRIB3 (607898), and VEGFA (192240). Knockdown of USP16 by siRNA impaired the responsiveness of all induced targets in at least 1 siRNA condition, and 4 targets (ASNS, CEBPB, SLC7A5, and TRIB3) exhibited reduced inducibility by both USP16 siRNAs. The 7 genes associated to rs2831649 had been shown to respond to amino acid deprivation, and some to the unfolded protein stress response (UPR), which is induced by oxidized phospholipid in epithelial cells. Romanoski et al. (2010) concluded that variation at GxE 'hotspot' SNP rs2831649 modulates the oxidized phospholipid change in UPR genes through the action of USP16. Additionally, a striking example of a local GxE interaction was observed in this study for FGD6 (613520).

Adorno et al. (2013) found that in Ts65Dn mice, which are trisomic for 132 genes homologous to genes on human chromosome 21, triplication of Usp16 reduces the self-renewal of hematopoietic stem cells and the expansion of mammary epithelial cells, neuroprogenitors, and fibroblasts. In addition, Usp16 is associated with decreased ubiquitination of Cdkn2a (600160) and accelerated senescence in Ts65Dn fibroblasts. Usp16 can remove ubiquitination from histone H2A (see 613499) on lys119, a critical mark for the maintenance of multiple somatic tissues. Downregulation of Usp16, either by mutation of a single normal Usp16 allele or by short interfering RNAs, largely rescues these defects. Furthermore, in human tissues overexpression of USP16 reduces the expansion of normal fibroblasts and postnatal neural progenitors, whereas downregulation of USP16 partially rescues the proliferation defects of Down syndrome (190685) fibroblasts. Adorno et al. (2013) suggested that USP16 has an important role in antagonizing the self-renewal and/or senescence pathways in Down syndrome and could serve as an attractive target to ameliorate some of the associated pathologies.