Role of Deubiquitinating Enzymes in DNA Repair

Abstract

Both proteolytic and nonproteolytic functions of ubiquitination are essential regulatory mechanisms for promoting DNA repair and the DNA damage response in mammalian cells. Deubiquitinating enzymes (DUBs) have emerged as key players in the maintenance of genome stability. In this minireview, we discuss the recent findings on human DUBs that participate in genome maintenance, with a focus on the role of DUBs in the modulation of DNA repair and DNA damage signaling. DEUBIQUITINATING ENZYMES Safeguarding the genome from genotoxic stress is critical for cell survival and for preventing various human diseases, including cancer. DNA repair or DNA damage responses are under exquisite control and must be accurately and rapidly executed when genome integrity is challenged. Understanding the molecular mechanisms and regulation of critical DNA repair and damage response factors in mammalian cells will provide insight into the pathogenesis of human diseases and aid in the development of therapeutics. Ubiquitination is a posttranslational modification event that allows for rapid and dynamic changes in a protein fate or function. The ubiquitin-proteasome system (UPS) is an essential posttranslational regulatory mechanism that permeates into diverse biological processes, including the DNA repair and damage response pathways. While the role of ubiquitin in mediating controlled degradation/proteolysis of specific proteins is well established, nonproteolytic functions of ubiquitination have also emerged as important players in signaling pathways that often exist in parallel with the UPS. Deubiquitinating enzymes (DUBs), responsible for reversing the ubiquitination reaction by removing covalently attached ubiquitin molecules from substrates or polyubiquitinated chains, have recently exploded onto the ubiquitin field as key regulators of both the UPS and of the nonproteolytic functions of ubiquitination. Thus, DUBs exert profound influence on many cellular pathways, including one of the best-studied biological processes involving DNA repair and damage response in mammalian cells.There are approximately 95 DUBs encoded by the human genome, which fall into one of the five subclasses: ubiquitin C-terminal hydrolases (UCHs), ubiquitin-specific proteases (USPs), Machado-Joseph domain-containing proteins (MJDs), Otubain domain-containing proteases (OTUs), and JAMM (JAB1/MPN/ Mov34) proteases (1, 2). Ubiquitin has seven internal lysine residues (Lys6,, each providing sites for the generation of an isopeptide bond with the carboxy terminus of another ubiquitin to form ubiquitin polymers, otherwise known as polyubiquitination. Linear ubiquitin chains can also be generated when the amino-terminal methionine (Met) of ubiquitin (Met1) forms a peptide bond with the carboxy-terminal glycine (Gly) of ubiquitin. As different types of polyubiquitin polymers adopt different conformations (3), it is not surprising that many DUBs show some degree of specificity toward differentially linked polyubiquitination, each of which results in a different physi...

The Evolution and Functional Diversification of the Deubiquitinating Enzyme Superfamily

“…2014; Citterio 2015; Kee and Huang 2015). Figure 6 illustrates DUB paralog involvement in DSB repair from an evolutionary perspective.Several instances of postduplicative innovations are apparent.…”

Mechanisms of regulation and diversification of deubiquitylating enzyme function

“…Post-translational attachment of ubiquitin, or ubiquitylation, controls most intracellular processes, including protein turnover, intracellular signalling, endocytosis and the DNA damage response (Clague and Urbe, 2017;Heideker and Wertz, 2015;Kee and Huang, 2015). Ubiquitin is most often conjugated to lysine residues of target proteins in a reaction catalysed by an enzymatic cascade that involves the E1 activating, E2 conjugating and E3 ligating enzymes.…”

The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair

“…Deubiquitinating enzymes (DUBs) have emerged as an important class of regulators of the UPS. 6 By removing covalently attached ubiquitin molecules from substrates or polyubiquitinated chains, DUBs act as balancers of the ubiquitinationproteasome system. USP1, initially identified as a deubiquitinase of FANCD2, 7 is an essential component of the Fanconi Anemia (FA) DNA repair pathway.…”