The role of Y-family polymerase in aberrant DNA replication and genomic instability

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K06826
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Gunma University
• Principal Investigator: Yamashita Takayuki 群馬大学, 生体調節研究所, 教授 (10166671)
• Co-Investigator(Renkei-kenkyūsha): ODA Tsukasa 群馬大学, 生体調節研究所, 助教 (10323643) ; SEKIMOTO Takayuki 群馬大学, 生体調節研究所, 助教 (20436322)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: がん遺伝子 / DNA複製 / DNA損傷 / DNAポリメラーゼ / 損傷乗り越えDNA合成

Outline of Final Research Achievements

Growth of neoplastic cells relies on their tolerance to oncogene-induced replication stress (RS). Translesion synthesis (TLS) plays a critical role in cellular tolerance to various types of RS by employing specialized polymerases. Here, we report that Polη, a Y-family TLS polymerase, promotes cellular tolerance to Myc-induced RS. Polη was recruited to Myc-induced RS sites, and Polη depletion enhanced the Myc-induced slowing and stalling of replication forks and the subsequent generation of double-strand breaks (DSBs). In the absence of Polη, Myc-induced DSB formation depended on MUS81-EME2 (the S-phase specific endonuclease complex), and concomitant depletion of MUS81-EME2 and Polη enhanced RS and cell death in a synergistic manner. Collectively, these results indicate that Polη alleviates the Myc-induced RS, and highlight the possibility of synthetic sick or lethal interaction between Polη and MUS81-EME2 in cells experiencing Myc-induced RS.

Free Research Field

DNA損傷応答