Spartan deficiency causes accumulation of Topoisomerase 1 cleavage complexes and tumorigenesis

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• Germline mutations in the SPRTN gene cause Ruijs-Aalfs syndrome (RJALS), a rare disorder characterized by premature aging, genome instability, and early-onset liver cancer.
• The SPRTN gene encodes the Spartan protein, a nuclear metalloprotease crucial for repairing DNA-protein crosslinks (DPCs).
• While Sprtn-deficient mice exhibit progeroid phenotypes, their susceptibility to DPC repair defects and spontaneous tumors remains unclear.

Purpose of the Study:

• To investigate the role of Spartan in DNA-protein crosslink (DPC) repair and tumor suppression.
• To determine if reduced Spartan levels in a hypomorphic mouse model lead to DPC accumulation, DNA damage, and spontaneous tumorigenesis.

Main Methods:

• Analysis of DPC accumulation in the livers of Sprtn hypomorphic mice.
• Assessment of DNA damage, aneuploidy, and spontaneous tumor development in these mice.
• Utilized a Sprtn hypomorphic mouse model to study Spartan function.

Main Results:

• Sprtn hypomorphic mouse livers showed accumulation of DPCs, specifically those involving Topoisomerase 1 covalently linked to DNA.
• These mice exhibited increased DNA damage and aneuploidy.
• Significant spontaneous tumorigenesis was observed in the livers of Sprtn hypomorphic mice.

Conclusions:

• Partial loss of Spartan function impairs the repair of DNA-protein crosslinks.
• Reduced Spartan levels compromise tumor suppression, leading to spontaneous liver cancer.
• These findings highlight Spartan's critical role in maintaining genome stability and preventing cancer.