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:30595436). 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 (By similarity). Associates with the DNA replication machinery and specifically removes DPCs during DNA synthesis (By similarity). Acts as a pleiotropic protease for DNA-binding proteins cross-linked with DNA, such as top1, top2a, histones H3 and H4 (By similarity). Mediates degradation of DPCs that are not ubiquitinated, while it is not able to degrade ubiquitinated DPCs (PubMed:30595436). SPRTN activation requires polymerase collision with DPCs followed by helicase bypass of DPCs (PubMed:30595436). May also act as a 'reader' of ubiquitinated pcna: 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 (By similarity). Acts as a regulator of translesion DNA synthesis by recruiting vcp/p97 to sites of DNA damage (By similarity). DNA-binding activates the protease activity: single-stranded DNA-binding specifically activates ability to cleave covalent DNA-protein cross-links (DPCs) (By similarity). In contrast, double-stranded DNA-binding specifically activates autocatalytic cleavage, and subsequent inactivation (By similarity). Homodimer. Localizes to sites of UV damage via the PIP-box (By similarity). Recruited to stalled replication forks at sites of replication stress (By similarity). The UBZ4-type zinc fingers mediate 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. Belongs to the Spartan family. Extended N-terminus. Extended N-terminus.