DNA–protein crosslink proteases in genome stability

Abstract

Proteins covalently attached to DNA, also known as DNA–protein crosslinks (DPCs), are common and bulky DNA lesions that interfere with DNA replication, repair, transcription and recombination. Research in the past several years indicates that cells possess dedicated enzymes, known as DPC proteases, which digest the protein component of a DPC. Interestingly, DPC proteases also play a role in proteolysis beside DPC repair, such as in degrading excess histones during DNA replication or controlling DNA replication checkpoints. Here, we discuss the importance of DPC proteases in DNA replication, genome stability and their direct link to human diseases and cancer therapy.

The protease SPRTN and SUMOylation coordinate DNA-protein crosslink repair to prevent genome instability

“…The former mechanism involves DNA-dependent metalloproteases, SPRTN in metazoans and Wss1 in yeast ( Lopez-Mosqueda et al., 2016 ; Maskey et al., 2017 ; Mórocz et al., 2017 ; Stingele et al., 2014 , 2016 ; Vaz et al., 2016 ), or the proteasome ( Larsen et al., 2019 ; Sparks et al., 2019 ; Sun et al., 2020 ). In addition to SPRTN, several proteases, such as ACRC, also known as germ cell nuclear antigen (GCNA), FAM111A and FAM111B, and DDI1 and DDI2, have recently been discovered and linked to DPC proteolysis repair (reviewed in Ruggiano and Ramadan, 2021a ). However, among them, SPRTN is the only essential gene in cells, indicating the crucial role of the protease SPRTN in DPC repair, embryogenesis, and cell survival.…”

Enzymatic bypass of an N6-deoxyadenosine DNA–ethylene dibromide–peptide cross-link by translesion DNA polymerases

“…Covalent DNA-protein cross-links are bulky lesions and can be toxic if left unrepaired (2); they are formed from both exogenous and endogenous sources. Accumulation of these cross-links has been associated with aging, cancer, neurodegeneration, and Ruijs-Aalfs syndrome (2)(3)(4)(5)(6), and there has been considerable interest in both DNA-protein cross-links and proteases that can act on them (6). Several laboratories have shown that both reversible and irreversible DNA-protein cross-links can be formed under physiological conditions, that there are DNA-stimulated proteases that can act on these, and that DNA-protein cross-links can be bypassed and can miscode (2,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19).…”

“…The activity of these enzymes is limited by substrate accessibility, suggesting that the adduct needs first to be hydrolyzed to a peptide (28). Recently DNA-activated proteases (6) and the proteasome have been suggested to be involved in proteolysis by cleaving large DNA-protein cross-links to DNA-peptide cross-links (18,29,30). Some DNA-dependent proteases bind to ubiquitin, or small ubiquitin-like modifier (SUMO), indicative of a role for posttranslational modification in proteolysis (31)(32)(33).…”

N-Terminomics Strategies for Protease Substrates Profiling

“…Based on their catalytic activity, proteases are classified into six distinct classes: serine, cysteine, threonine, glutamic, aspartic, and metalloproteases [ 4 ]. Proteases are central to numerous biological pathways and play a vital role in regulating many signaling processes, such as cell-cycle progression [ 5 ], cell proliferation [ 6 ], cell death [ 7 ], DNA replication [ 8 ], tissue remodeling [ 9 ], hemostasis [ 10 ], wound healing [ 11 ], and immune responses [ 11 ]. Consistent with their essential roles, alterations in proteolytic systems result in multiple pathological conditions, including cancer [ 12 ], neurodegenerative disorders [ 13 ], infections [ 13 ], allergies [ 14 ], blood clotting disorders [ 15 ], and cardiovascular diseases [ 16 ].…”