Elucidation of spatiotemporal control mechanism of dead cell DNA degrading enzymes by phase separation

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07086
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Tokyo University of Science
• Principal Investigator: Mizuta Ryushin 東京理科大学, 研究推進機構生命医科学研究所, 教授 (50297628)
• Co-Investigator(Kenkyū-buntansha): 北村 大介 東京理科大学, 研究推進機構生命医科学研究所, 教授 (70204914)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: DNase γ / DNase1L3 / DNase 1 / 相分離 / cfDNA / 抗腫瘍効果 / クロマチン / Histone H1

Outline of Final Research Achievements

DNase γ (also known as DNase1L3) is a DNA-degrading enzyme that belongs to the DNase 1 family and is present in the bloodstream together with DNase 1. The leaked chromatin is first largely cleaved by DNase γ and released into the bloodstream as cell-free DNA (cfDNA). It is then finely cut by DNase 1, but the mechanism of its temporal and spatial differentiation was unknown. We found that the difference in affinity to phase-separated chromatin creates the difference in its differentiation, and that DNase 1 is also involved in the generation of cfDNA. Furthermore, experiments with gene-deficient mice revealed that DNase γ has antitumor activity.

Free Research Field

免疫学、分子生物学

Academic Significance and Societal Importance of the Research Achievements

この研究は20年にわたるDNase γを中心とした死細胞DNAの分解研究の集大成であるとともに、DNA分解と相分離の関連を見出した事により、新たな展開の道を開いた。より普遍的には、生命現象の根本に相分離を位置づけ、個別の事象を統一的に捉えなおすきっかけになることが期待される。またDNase γの抗腫瘍活性の発見は新規治療戦略の創出という点で、臨床的に意義がある。