DNA-dependent metalloendopeptidase that mediates the proteolytic cleavage of covalent DNA-protein cross-links (DPCs) during DNA synthesis, thereby playing a key role in maintaining genomic integrity (PubMed:27852435, PubMed:27871366, PubMed:27871365, PubMed:32649882, PubMed:30893605). DPCs are highly toxic DNA lesions that interfere with essential chromatin transactions, such as replication and transcription, and which are induced by reactive agents, such as UV light or formaldehyde (PubMed:27852435, PubMed:27871366, PubMed:27871365, PubMed:32649882). Associates with the DNA replication machinery and specifically removes DPCs during DNA synthesis (PubMed:27852435, PubMed:27871366, PubMed:27871365, PubMed:32649882). Acts as a pleiotropic protease for DNA-binding proteins cross-linked with DNA, such as TOP1, TOP2A, histones H3 and H4 (PubMed:27871366). Mediates degradation of DPCs that are not ubiquitinated, while it is not able to degrade ubiquitinated DPCs (By similarity). SPRTN activation requires polymerase collision with DPCs followed by helicase bypass of DPCs (By similarity). Involved in recruitment of VCP/p97 to sites of DNA damage (PubMed:22902628, PubMed:23042605, PubMed:23042607, PubMed:32152270). Also acts as an activator of CHEK1 during normal DNA replication by mediating proteolytic cleavage of CHEK1, thereby promoting CHEK1 removal from chromatin and subsequent activation (PubMed:31316063). Does not activate CHEK1 in response to DNA damage (PubMed:31316063). May also act as a 'reader' of ubiquitinated PCNA: recruited to sites of UV damage and interacts with ubiquitinated PCNA and RAD18, the E3 ubiquitin ligase that monoubiquitinates PCNA (PubMed:22681887, PubMed:22894931, PubMed:22902628, PubMed:22987070). Facilitates chromatin association of RAD18 and is required for efficient PCNA monoubiquitination, promoting a feed-forward loop to enhance PCNA ubiquitination and translesion DNA synthesis (PubMed:22681887). DNA-binding activates the protease activity: single-stranded DNA-binding specifically activates ability to cleave covalent DNA-protein cross-links (DPCs) (PubMed:27871366, PubMed:27871365, PubMed:30893605). In contrast, double-stranded DNA-binding specifically activates autocatalytic cleavage, and subsequent inactivation (PubMed:27852435, PubMed:27871365, PubMed:30893605). Homodimer (PubMed:30893605). Interacts (VIA PIP-box) with PCNA (when ubiquitinated) (PubMed:22894931, PubMed:22902628, PubMed:22681887, PubMed:23042605, PubMed:23042607, PubMed:22987070, PubMed:27084448). Interacts (via its SHP-box) with VCP/p97 (PubMed:22902628, PubMed:23042605, PubMed:23042607). Interacts with RAD18 (PubMed:22681887). Interacts with KCTD13 and POLD3 (PubMed:22902628). Localizes to sites of UV damage via the PIP-box (PubMed:22894931, PubMed:23042605). Recruited to stalled replication forks at sites of replication stress following deubiquitination (PubMed:22894931, PubMed:23042605, PubMed:22987070, PubMed:27871365, PubMed:32649882). CHEK1 stimulates recruitment to chromatin (PubMed:31316063). Predominantly expressed during S- and G2-phases and early M-phase (PubMed:23042605). It then drops, and is probably degraded by the APC/C complex (PubMed:23042605). The PIP-box mediates the interaction with PCNA, while the UBZ4-type zinc finger mediates binding to 'Lys-48'- and 'Lys-63'-linked polyubiquitin. Autocatalytically cleaved in response to double-stranded DNA-binding: autocatalytic cleavage takes place in trans and leads to inactivation. Monoubiquitinated; monoubiquitination promotes exclusion from chromatin (PubMed:27871365, PubMed:32649882). Deubiquitinated by VCPIP1: deubiquitination is required for subsequent acetylation and recruitment to chromatin and DNA damage sites (PubMed:27871365, PubMed:32649882). Acetylated following deubiquitination by VCPIP1, leading to recruitment to chromatin and DNA damage sites. Phosphorylation by CHEK1 promotes recruitment to chromatin. The disease is caused by variants affecting the gene represented in this entry. Belongs to the Spartan family.