RECQ1 Promotes Stress Resistance and DNA Replication Progression Through PARP1 Signaling Pathway in Glioblastoma.

Jing Zhang,Min Liu,Siyi Xu,Bingsong Huang,Hao Lian,Chunlong Zhong,Kui Chen,Mu Chen,Ying Pang,Lei Zhu

doi:10.3389/fcell.2021.714868

Abstract

Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor, and patients with GBM have a median survival of 20 months. Clinical therapy resistance is a challenging barrier to overcome. Tumor genome stability maintenance during DNA replication, especially the ability to respond to replication stress, is highly correlated with drug resistance. Recently, we identified a protective role for RECQ1 under replication stress conditions. RECQ1 acts at replication forks, binds PCNA, inhibits single-strand DNA formation and nascent strand degradation in GBM cells. It is associated with the function of the PARP1 protein, promoting PARP1 recruitment to replication sites. RECQ1 is essential for DNA replication fork protection and tumor cell proliferation under replication stress conditions, and as a target of RECQ1, PARP1 effectively protects and restarts stalled replication forks, providing new insights into genomic stability maintenance and replication stress resistance. These findings indicate that tumor genome stability targeting RECQ1-PARP1 signaling may be a promising therapeutic intervention to overcome therapy resistance in GBM.

Highlights

Glioblastoma (GBM) is the most common, aggressive adult primary brain tumor and is associated with profound genomic heterogeneity and limited cure development to date (Stupp et al, 2017)
We show that RECQ1 depletion results in increased nascent strand degradation and fork stalling, DNA double-strand breaks (DSBs) and a decreased cell proliferation rate under replication stress, supporting the notion that RECQ1 plays a specific role in the maintenance of genomic stability
Because RECQ1 was found to be overexpressed in glioblastomas, we investigated the sensitivity of glioblastoma cells to temozolomide (TMZ), which is an anticancer alkylating agent commonly used for the treatment of human brain tumors

Summary

Introduction

Glioblastoma (GBM) is the most common, aggressive adult primary brain tumor and is associated with profound genomic heterogeneity and limited cure development to date (Stupp et al, 2017). RECQ1-PARP1 Regulation in Glioblastoma Progression replication is critical for the maintenance of genomic integrity, driving functional “protection” for the survival of rapidly dividing tumor cells, which leads to resistance to cancer drug therapy. Human RecQ helicases (WRN, BLM, RECQ4, RECQ5, and RECQ1) play critical roles in protecting and stabilizing the genome (Hickson, 2003; Opresko et al, 2004). Depending on their ability to unwind various DNA structures, multiple cellular functions have been associated with RecQ proteins, including those with roles in stabilizing damaged DNA replication forks, telomere maintenance, and homologous recombination (Sharma et al, 2006; Bohr, 2008; Ouyang et al, 2008). As the most abundant of the five human RecQ proteins, the clinical importance of RECQ1 has only been partially revealed, the currently mysterious, unknown, unique, and important roles of RECQ1 in cellular DNA metabolism need to be discovered

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