Mechanism for repairing of double-strand breaks in heterochromatin

2022 Fiscal Year Final Research Report

• Project/Area Number: 19H03156
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 43010:Molecular biology-related
• Research Institution: Osaka University
• Principal Investigator: Obuse Chikashi 大阪大学, 大学院理学研究科, 教授 (00273855)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: DNA損傷修復

Outline of Final Research Achievements

Two pathways are known to repair double-strand breaks caused by radiation and other factors on heterochromatin: non-homologous end joining repair (NHEJ) and homologous recombination repair (HR). The choice between these is important from the perspective of preventing chromosome translocations and deletions when there are repeated sequences or similar base sequences where heterochromatin is formed. In this pathway selection, it is known that a protein called RIF1 inhibits the trimming of damage sites necessary for HR and promotes NHEJ. Through this project, we found that PP1 binds to RIF1, and the enzymatic activity that trims the damage sites is inhibited by the activity of this PP1, shedding light on part of the mechanism of DNA damage repair pathway selection.

Free Research Field

分子細胞生物学

Academic Significance and Societal Importance of the Research Achievements

DNA損傷修復に関わる遺伝子の変異はさまざまな疾患の原因となることが知られている。例えば、RIF1は、乳がん、卵巣がんの原因遺伝子であるBRCA1と深い関わりがある。RIF1の機能に問題があると、NHEJによる修復への誘導が起こらないため、BRCA1がない状態でも異常なHR経路が発動され、抗がん剤耐性細胞になることが実験的に証明されている。今回発見したRIF1と結合しているPP1の働きは、シールディンとともにRIF1のDNA損傷修復における機能そのものであるため、抗がん剤耐性細胞が出現する仕組みや、解決への糸口になると考えられる。