PML3 Orchestrates the Nuclear Dynamics and Function of TIP60

He Huang,Kang-Sang Chang,Haixiang Hu,Jianping Lan,Quan Wu,Xuebiao Yao,Zhiyong Wang,Chibuzo Emenari

doi:10.1074/jbc.m807590200

Abstract

The promyelocytic leukemia (PML) protein is a major component to govern the PML nuclear body (NB) assembly and function. Although it is well defined that PML NB is a site recruiting sumoylated proteins, the mechanism by which PML protein regulates the process remains unclear. Here we show that PML3, a specific PML isoform, interacts with and recruits TIP60 to PML NBs. Our biochemical characterization demonstrates that PML3 physically interacts with TIP60 via its N-terminal 364 amino acids. Importantly, this portion of TIP60 is sufficient to target to the PML NBs, suggesting that PML3-TIP60 interaction is sufficient for targeting TIP60 to the NBs. The PML3-TIP60 interaction is specific, since the region of TIP60 binding is not conserved in other PML isoforms. The physical interaction between PML3 and TIP60 protects TIP60 from Mdm2-mediated degradation, suggesting that PML3 competes with MDM2 for binding to TIP60. Fluorescence recovery after photobleaching analysis indicates that the PML3-TIP60 interaction modulates the nuclear body distribution and mobility of TIP60. Conversely, the distribution and mobility of TIP60 are perturbed in PML3-deficient cells, accompanied by aberrations in DNA damage-repairing response. Thus, PML3 orchestrates the distribution, dynamics, and function of TIP60. Our findings suggest a novel regulatory mechanism by which the PML3 and TIP60 tumor suppressors cooperate to ensure genomic stability.

Highlights

The histone acetyltransferase TIP60 regulates the DNA damage response following genotoxic stress by acetylating histone and remodeling chromatin [1,2,3,4,5]
PML3 Recruits TIP60 to the Nuclear Bodies—It is well defined that TIP60 co-localizes with p53 in promyelocytic leukemia (PML) nuclear bodies (PML nuclear body (NB)) to share similar biological significance, and PML3 recruits p53 to the
Taking into account our latest observation that UV radiation promotes the translocation of TIP60 to the PML NBs [15], we are intrigued to investigate whether PML3 assist the redistribution of TIP60 to PML NBs

Summary

Introduction

The histone acetyltransferase TIP60 regulates the DNA damage response following genotoxic stress by acetylating histone and remodeling chromatin [1,2,3,4,5]. The kinase ataxia telangiectasia-mutated (ATM) activation is dependent on its acetylation by TIP60 in response to DNA double break repair [10], indicating that TIP60 plays crucial roles in DNA damage response. P53 is recruited by sumoylated TIP60 to PML NBs in response to UV irradiation [15], suggesting that PML NBs are an essential location to monitor TIP60 function. Numerous dynamic components of PML NBs, including ATM, Chk, p53, TIP60, Mdm, Daxx, SUMO-1, and Ubc, prominently implicate a role for PML NBs in DNA repair, apoptosis, gene regulation, and post-translational modification [18, 19]. In acute promyelocytic leukemia cells, during treatment with therapeutic agents, such as As2O3, the disrupted PML NBs reorganize to a normal NB pattern [21], suggesting that PML NBs are potential targets for acute promyelocytic leukemia therapy

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Conclusion