{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSPRTN is a specialized, DNA‐dependent metalloprotease that plays a central role in maintaining genome integrity by cleaving DNA–protein crosslinks (DPCs) that would otherwise block replication fork progression. Activated by binding to specific DNA structures that combine single‐ and double‐stranded features, SPRTN carries out proteolysis of diverse DNA‐bound substrates during S phase, thereby directly resolving cytotoxic lesions and preventing replication stress. In addition, its catalytic activity is tightly controlled via DNA recognition and regulatory domains that restrict cleavage to stalled replication intermediates. Dysfunction in this replication‐coupled DPC repair pathway, as observed in Ruijs–Aalfs syndrome patients, underlies genomic instability, premature aging, and cancer predisposition."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its direct proteolytic function, SPRTN (also known as Spartan or DVC1) is intricately involved in regulating DNA damage tolerance pathways. It is recruited to stalled replication forks via its PCNA‐interacting peptide (PIP) box and ubiquitin‐binding domains, engaging with ubiquitylated PCNA and other factors such as the p97 segregase. Through these interactions, SPRTN modulates the switch between replicative and specialized translesion synthesis (TLS) polymerases, preventing excessive mutagenesis while promoting lesion bypass. Its activity is further fine‐tuned by ubiquitin signals that induce controlled auto‐proteolysis and coordinate feed‐forward mechanisms to stabilize RAD18 and maintain proper TLS regulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its central role in replication‐coupled DPC repair and TLS coordination, SPRTN contributes to broader aspects of genome maintenance and cellular homeostasis. It collaborates in the processing of TOP1 cleavage complexes through interactions with factors such as TEX264, and is involved in regulating the integrity of other DNA repair complexes, including those involved in double‐strand break repair. Furthermore, aberrant SPRTN activity has been linked to replication stress in non‐replicative contexts and perturbed endoplasmic reticulum stress responses, which together contribute to early onset hepatocellular carcinoma and other progeroid phenotypes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Julian Stingele, Roberto Bellelli, Ferdinand Alte, et al. 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