USP19 deubiquitinates HDAC1/2 to regulate DNA damage repair and control chromosomal stability.

Min Wu,Bo Tan,Wei-Na Zhang,Guang Wang,Hai-Qing Tu,Yan Chang,Jie Zhou,Li Wang,Rui Mu

doi:10.18632/oncotarget.11116

Abstract

Excessive accumulation of DNA damage will generate chromosome stress, leading to various chromosome abnormalities such as chromatin bridge and result in genomic instability. Orchestra procession and regulation of DNA damage repair are vital for keeping genome stability. Despite of the key role of HDAC1/2 in double strand break (DSB) repair, the regulation for their mode of action is less well understood. In this study, we found that deubiquitination enzymes USP19 physically interacts with HDAC1/2 and specifically regulate their K63-linked ubiquitination, which might be crucial for regulation of HDAC1/2 activity in DNA damage repair. Notably, we found that USP19 trans-locate into nucleus upon IR irradiation and is indispensable for normally DNA damage response. In addition, we showed that USP19 play critical role in preventing anaphase bridge formation through regulating DNA damage repair process. Furthermore, the expression level of USP19 is commonly lower or deleted in several types of tumor. These results indicated that USP19 is a key factor in modulating DNA damage repair by targeting HDAC1/2 K63-linked ubiquitination, cells with deletion or decreased expression of USP19 might cause genome instability and even contribute to tumorigenesis.

Highlights

The exposure of cells to various genotoxic stresses will lead to DNA damage which would jeopardize the genome integrity
In a separate mitosis screening study, we found that USP19 knockdown in HeLa cells could result in obvious increase of chromosome segregation errors, which could be confirmed by two separate USP19 siRNA (Figures 1A1C)
The K48-linked ubiquitination of HDAC1/2 had been reported by some groups [25], little is known about the regulation of K63-linked ubiquitination of HDAC1/2

Summary

Introduction

The exposure of cells to various genotoxic stresses will lead to DNA damage which would jeopardize the genome integrity. Double-strand breaks (DSBs) is the most consequential types of DNA damage and are mainly repaired by either homologous recombination (HR), which is limited to the S and G2 phase of cell cycle, or non-homologous endjoining (NHEJ), which operates throughout the cell cycle [2]. Anaphase bridge, which is usually happened in the case of genomic instability will be induced if doublestrand breaks (DSB) could not be normally repaired due to some kind of defect in DNA repair [3, 4]. Accumulation of DNA damage in cells would lead to chromosome mis-segregation, which may entail chromatin/anaphase bridges, prevent normal cytokinesis and high rates of chromosomal mis-segregation would cause chromosome instability(CIN), which is a common characterize for majority of human cancer [5, 6]. DNA repair pathway which is tightly controlled by several important factors is vital to maintain genome stability

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Conclusion