Depletion of NK6 Homeobox 3 (NKX6.3) causes gastric carcinogenesis through copy number alterations by inducing impairment of DNA replication and repair regulation

Jung Hwan Yoon,Suk Woo Nam,Jeong Kyu Kim,Duane T Smoot,Hassan Ashktorab,Jung Woo Eun,Won Sang Park

doi:10.1038/s41389-021-00365-4

Abstract

Genomic stability maintenance requires correct DNA replication, chromosome segregation, and DNA repair, while defects of these processes result in tumor development or cell death. Although abnormalities in DNA replication and repair regulation are proposed as underlying causes for genomic instability, the detailed mechanism remains unclear. Here, we investigated whether NKX6.3 plays a role in the maintenance of genomic stability in gastric epithelial cells. NKX6.3 functioned as a transcription factor for CDT1 and RPA1, and its depletion increased replication fork rate, and fork asymmetry. Notably, we showed that abnormal DNA replication by the depletion of NKX6.3 caused DNA damage and induced homologous recombination inhibition. Depletion of NKX6.3 also caused copy number alterations of various genes in the vast chromosomal region. Hence, our findings underscore NKX6.3 might be a crucial factor of DNA replication and repair regulation from genomic instability in gastric epithelial cells.

Highlights

Genome stability is necessary for the integrity of human cells that are exposed continuously to the genotoxic agent
Depletion of NKX6.3 leads to DNA copy number alterations (CNAs) Since double-strand breaks (DSBs) repair abnormalities induced by DNA replication stress (RS) are known to cause genomic instability, including CNAs [13,14,15], we investigated whether depletion of NKX6.3 can induce CNAs in gastric epithelial cells
We provide evidences showing that NKX6.3 depletion could lead to DNA RS, which results in genomic instability

Summary

Introduction

Genome stability is necessary for the integrity of human cells that are exposed continuously to the genotoxic agent. DNA repair is an important defense mechanism, maintaining genome integrity. Defective DNA repair can lead to cancer development by inducing mutations and chromosomal aberrations [1]. We reported that NKX6.3, which showed frequently lost or reduced expression in gastric cancers, acted as a gastric tumor suppressor by inhibiting cell proliferation and inducing apoptosis [8, 9]. It protects gastric epithelial cells against the expression of the AICDA/APOBEC family, NFκB, and CBFβ gene expression, known to generate genome-wide somatic mutations and the accumulation of genetic alterations in gastric epithelial cells [10]

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