| Summary: | 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, <i>RNASEH2A</i> being the catalytic subunit. <i>RNASEH2A</i> expression levels have been shown to be upregulated in transformed and cancer cells. In this study, we used a bioinformatics approach to identify <i>RNASEH2A</i> co-expressed genes in different human tissues to underscore biological processes associated with <i>RNASEH2A</i> expression. Our analysis shows functional networks for <i>RNASEH2A</i> 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 <i>RNASEH2A</i> but not for the other two subunits of RNase H2 in cell proliferation. Mass spectrometry analysis of <i>RNASEH2A</i>-bound proteins identified players functioning in cell cycle regulation. Additional bioinformatic analysis showed that <i>RNASEH2A</i> 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.
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