Study on the role for HERC2 in the response to replication stress

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08676
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: St. Marianna University School of Medicine
• Principal Investigator: Wu Wenwen 聖マリアンナ医科大学, 医学研究科, 准教授 (10434408)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: HERC2 / BLM / RPA / DNA複製ストレス応答 / グアニン4重鎖

Outline of Final Research Achievements

In this study, we found that an HECT E3 ligase HERC2 interacts with RecQ helicases BLM and WRN, and is a master regulator of G4 suppression. HERC2 depletion resulted in elevated level of sister chromatid exchange and in a dramatic G4 accumulation in a manner epistatic to depletion of BLM and WRN. Inactivation of E3 ligase activity of HERC2 by Cas9/CRISPR-mediated gene editing demonstrates an essential role of the activity to prevent the phenotype. Mechanistically, HERC2 regulates the interaction of the helicases with replication protein A (RPA), which is known to support the helicase activity to unfold G4s. In addition, HERC2 regulates ATR-phosphorylated RPA2 levels through induction and degradation. Importantly, the HERC2 dysfunctions sensitize cells to G4 stabilizers telomestatin and pyridostatin. Given that the HERC2 expression is frequently reduced in many types of cancers, the G4 accumulation by HERC2 deficiency may provide a therapeutic target for the G4 stabilizers.

Free Research Field

腫瘍学(腫瘍生物学)、基礎医学(病態医化学)

Academic Significance and Societal Importance of the Research Achievements

HERC2あるいはそのE3活性の欠失により、DNAヘリカーゼであるBLMとWRNの機能が損なわれてG4が蓄積し、細胞はG4安定化剤であるピリドスタチンおよびテロメスタチンに対して高い感受性を示した。多くのタイプのがんにおいてHERC2の発現が減少していることから、HERC2の機能不全によるG4の蓄積はがん治療においてG4安定化剤の標的あるいは効果の指標となることが期待される。