Elucidation of the Mechanism of DNA Damage Toxicity Induction by Mutant TREX1 Causing Leukoencephalopathy and Its Inhibitory Molecules

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K20882
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0902:General internal medicine and related fields
• Research Institution: Niigata University
• Principal Investigator: Shoichiro Ando 新潟大学, 医歯学総合病院, 助教 (10918428)
• Project Period (FY): 2022-08-31 – 2024-03-31
• Keywords: RVCL-S / TREX1 / DNA二本鎖切断損傷 / 相同組換え修復 / 細胞老化

Outline of Final Research Achievements

We hypothesized that the pathogenesis of RVCL-S is due to abnormalities in DNA damage or its repair pathways and conducted a validation study. As a result, we found that the RVCL-S type mutant TREX1 induced DNA double-strand break (DSB) damage and caused cellular senescence in a manner dependent on its enzymatic activity and nuclear localization.
Additionally, we discovered that the RVCL-S type mutant TREX1 impaired homologous recombination repair (HDR), which contributes to DSB repair. Importantly, although the expression of normal TREX1 is tightly regulated and extremely low, it is highly expressed in patient tissues, and this expression of TREX1 is induced by the senescence-associated secretory phenotype (SASP).

Free Research Field

脳神経内科学

Academic Significance and Societal Importance of the Research Achievements

RVCL-S型変異TREX1がHDR抑制による二本鎖DNA切断修復異常によるDNA損傷毒性をきたすという病態機序仮説は、現在我々のみが保有する新規のものであり、学術的意義が高い。この病態機序仮説をもとに、これまで疾患修飾療法が全く存在しなかったRVCL-Sに対して、新規の治療戦略を提案することが可能である。RVCL-Sは希少疾患ではあるが、常染色体顕性遺伝性疾患であり、本疾患の治療可能性を見出すことは、社会的意義が大きい。