SPRTN, a DNA-dependent metalloprotease, is the essential enzyme for DNA-protein crosslink (DPC) proteolysis repair [1,2,3]. DPCs are harmful DNA lesions induced by various agents, and unrepaired DPCs can block DNA metabolic processes, leading to genome instability and cancer. SPRTN is involved in replication-coupled DPC repair and is also required for translesion DNA synthesis following DPC degradation [3]. Biallelic mutations in SPRTN cause Ruijs-Aalfs (RJALS) syndrome, characterized by hepatocellular carcinoma and segmental progeria, highlighting its significance in genome maintenance [3].

Sprtn-deficient MEF cells treated with ionizing radiation had higher levels of total DPCs and were more sensitive to hydrogen peroxide and other crosslinking agents [4]. SPRTN-deficient mice exhibit an accelerated aging phenotype and develop liver cancer early in life, suggesting its crucial role in preventing these disease conditions [4]. In human HCC tissue samples, alterations in SPRTN expression levels were found, and SPRTN interacts with the UPR sensor GRP78, with SPRTN-depleted cells showing increased sensitivity to ER stress, indicating its role in HCC development through the ER stress response [5].

In conclusion, SPRTN plays a vital role in maintaining genomic integrity by repairing DPCs. Studies using Sprtn-deficient mouse models have revealed its significance in preventing premature aging and liver cancer. Additionally, its role in the ER stress response provides new insights into HCC pathogenesis.