Abstract
MYC-induced nuclear antigen (MINA53) is a JmjC (jumonji C domain)-containing protein, which is highly expressed in many cancers including glioblastoma. We have revealed in our previous report that MINA53 is a poor prognostic indicator for glioblastoma patients, and knockdown of MINA53 could reduce glioblastoma malignancy. In this study, we found that MINA53 knockdown could decrease the DNA replication initiation in glioblastoma cells. Through further investigations, we revealed that MINA53 could regulate the expression of the CDC45-MCM-GINS (CMG) complex genes, which are vital for DNA replication initiation. Knockdown of MINA53 reduced the CMG genes expression and thus induced DNA replication stress and DNA damage. Furthermore, MINA53 knockdown diminished DNA damage response (DDR) by reducing the ATM/ATR-H2AX pathway activity and finally led glioblastoma cells to apoptosis and death. We further applied a genotoxic drug Doxorubicin and found that MINA53 deficiency sensitized glioblastoma cells to Doxorubicin. Our study reveals that MINA53 is involved in DNA replication initiation and DNA damage response, and provides support for MINA53 as a novel and potential therapeutic target for glioblastoma treatment.
Highlights
MYC-induced nuclear antigen (MINA531, known as Mdig[2], NO523, RIOX2) is a JmjCcontaining protein which is highly expressed in many cancers, such as pancreatic cancer[4], gastric adenocarcinoma[5], lung cancer[6,7], lymph cancer[8], colon cancer[9], esophageal squamous cell carcinoma[10], neuroblastoma[11], and cholangiocarcinoma[12]
Downregulation of MINA53 decreases DNA replication initiation in glioblastoma cells In our previous report, we found that knockdown of
These results suggested that knockdown of MINA53 decreases DNA replication initiation
Summary
MYC-induced nuclear antigen (MINA531, known as Mdig[2], NO523, RIOX2) is a JmjC (jumonji C domain)containing protein which is highly expressed in many cancers, such as pancreatic cancer[4], gastric adenocarcinoma[5], lung cancer[6,7], lymph cancer[8], colon cancer[9], esophageal squamous cell carcinoma[10], neuroblastoma[11], and cholangiocarcinoma[12]. DNA replication is a conserved cellular process which occurs exactly only once during cell-cycle progression for its initiation is tightly regulated[14]. The initiation of DNA replication can be divided into two steps: origin licensing and origin firing[15]. Origin licensing is the primary step which occurs in G1 phase. In this step, minichromosome maintenance protein (MCM) complex is recruited onto the origin DNA sequence to form DNA helicase[14,16,17,18]. In the process of origin firing, it is essential for DNA helicase to unwind double-stranded
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