Identification of global epigenetic alterations indispensable for malignant transformation and mediated by the RB-ATM pathway

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K06834
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Kanazawa University
• Principal Investigator: Awad Shamma 金沢大学, がん進展制御研究所, 助教 (50402839)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: RB / ATM / KAT3B / HDAC5 / Proteasome / Reprogramming proteins

Outline of Final Research Achievements

How the core reprogramming proteins are identified and recruited for degradation is unknown. Here, we demonstrate that functions of the retinoblastoma (RB) and the ataxia telangiectasia mutated (ATM) repress the pluripotency and self-renewal ability of the stem cell-like cells included in genetically modified mouse embryonic fibroblasts (MEFs) and A-T human adult fibroblasts (A-T HAFs) through acetylation-driven ubiquitination and subsequent proteasomal degradation of Oct3/4, Sox2, Klf4, Nanog and c-Myc (OSKNM) proteins. We discovered that RB recruits lysine acetyltransferase-3b (Kat3b) and inhibits the transcription of histone deacetylase-5 (Hdac5) whereas, ATM shuttles Hdac5 into the nucleus and serve as adaptor protein, which identify and assemble the acetylated-OSKNM proteins into ubiquitination complexes with the E3 ubiquitin ligase Uhrf1 or Fbxw7. These novel findings have important implications in regenerative medicine, neurodegenerative diseases and cancer.

Free Research Field

Stem cell biology