Gene Co-Expression Analysis of Human RNASEH2A Reveals Functional Networks Associated with DNA Replication, DNA Damage Response, and Cell Cycle Regulation

SIMPLE SUMMARY: RNASEH2A is the catalytic subunit of the ribonuclease (RNase) H2 ternary complex that plays an important role in maintaining DNA stability in cells. Recent studies have shown that the RNASEH2A subunit alone is highly expressed in certain cancer cell types. Via a series of bioinformatics approaches, we found that RNASEH2A is highly expressed in human proliferative tissues and many cancers. Our analyses reveal a possible involvement of RNASEH2A in cell cycle regulation in addition to its well established role in DNA replication and DNA repair. Our findings underscore that RNASEH2A could serve as a biomarker for cancer diagnosis and a therapeutic target. ABSTRACT: Ribonuclease (RNase) H2 is a key enzyme for the removal of RNA found in DNA-RNA hybrids, playing a fundamental role in biological processes such as DNA replication, telomere maintenance, and DNA damage repair. RNase H2 is a trimer composed of three subunits, RNASEH2A being the catalytic subunit. RNASEH2A expression levels have been shown to be upregulated in transformed and cancer cells. In this study, we used a bioinformatics approach to identify RNASEH2A co-expressed genes in different human tissues to underscore biological processes associated with RNASEH2A expression. Our analysis shows functional networks for RNASEH2A involvement such as DNA replication and DNA damage response and a novel putative functional network of cell cycle regulation. Further bioinformatics investigation showed increased gene expression in different types of actively cycling cells and tissues, particularly in several cancers, supporting a biological role for RNASEH2A but not for the other two subunits of RNase H2 in cell proliferation. Mass spectrometry analysis of RNASEH2A-bound proteins identified players functioning in cell cycle regulation. Additional bioinformatic analysis showed that RNASEH2A correlates with cancer progression and cell cycle related genes in Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA) Pan Cancer datasets and supported our mass spectrometry findings.