Elucidation of mechanisms ensuring optimal double-strand break number in meiotic cells

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02400
• 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: Kyoto University
• Principal Investigator: CARLTON Peter 京都大学, 生命科学研究科, 准教授 (20571813)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 減数分裂 / C. elegans / 染色体 / 二重鎖切断 / リン酸化制御 / キナーゼ / ホスファターゼ

Outline of Final Research Achievements

We have made significant progress in understanding how programmed DNA double-strand breaks are regulated in meiotic prophase. First, we found that the phosphatase PP4 and the DNA damage kinase ATR work in opposite directions to promote and suppress double-strand breaks in C. elegans. Second, we found evidence that PP4 and ATR act through a common substrate, the protein DSB-1. DSB-1 (called Rec114 in mammals) is an essential double-strand break cofactor. DSB-1 is hyperphosphorylated in the absence of PP4; conversely, it requires ATR kinase to become phosphorylated. Third, we found that non-phosphorylatable DSB-1 is hyperactive, able to rescue double-strand break defects in PP4 mutants as well as mutants in dsb-2, a paralog of DSB-1. Our results have revealed a new facet of double-strand break initiation, and explained our previous findings in PP4 mutants, and set the stage for continued investigation into how phosphorylation of DSB-1 prevents DNA breaks from occurring.

Free Research Field

減数分裂

Academic Significance and Societal Importance of the Research Achievements

Our research target DSB-1 (mammalian Rec114) has been under intense investigation in the past few years, and we have used the advantages of C. elegans to understand novel features of how it both promotes and restricts double-strand break activity; our work was published in Elife (2022).