TIP60 K430 SUMOylation Attenuates Its Interaction with DNA-PKcs in S-phase Cells: Facilitating Homologous Recombination and Emerging Target for Cancer Therapy

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2020 Aug 25

PMID 32832608

Citations 17

Authors

Shan-Shan Gao

Hua Guan

Shuang Yan

Sai Hu

Man Song

Zong-Pei Guo

Da-Fei Xie

Yike Liu

Xiaodan Liu

Shimeng Zhang

Ping-Kun Zhou

Affiliations

Soon will be listed here.

Abstract

Nonhomologous end joining (NHEJ) and homologous recombination (HR) are major repair pathways of DNA double-strand breaks (DSBs). The pathway choice of HR and NHEJ is tightly regulated in cellular response to DNA damage. Here, we demonstrate that the interaction of TIP60 with DNA-PKcs is attenuated specifically in S phase, which facilitates HR pathway activation. SUMO2 modification of TIP60 K430 mediated by PISA4 E3 ligase blocks its interaction with DNA-PKcs, whereas TIP60 K430R mutation recovers its interaction with DNA-PKcs, which results in abnormally increased phosphorylation of DNA-PKcs S2056 in S phase and marked inhibition of HR efficiency, but barely affects NHEJ activity. TIP60 K430R mutant cancer cells are more sensitive to radiation and PARP inhibitors in cancer cell killing and tumor growth inhibition. Collectively, coordinated regulation of TIP60 and DNA-PKcs facilitates HR pathway choice in S-phase cells. TIP60 K430R mutant is a potential target of radiation and PARPi cancer therapy.

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