REV3L and Associated Diseases
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Backgrounds of REV3L
The REV3L gene is located on chromosome 6q21 and is a human homologue of the Rev3 gene of Saccharomyces cerevisiae. It encodes the catalytic subunit of DNA polymerase, which is thought to be one of the major components of error-prone TLS. The REV3L gene appears to be universally expressed in normal and malignant human tissues, and its expression levels vary in different normal and tumor cell lines. DNA Directed Polymerase Zeta Catalytic Subunit (REV3L) has recently emerged as an important oncogene, which is responsible for translesional replication, this function makes REV3L a cancer susceptibility candidate gene. It plays a significant role in the cytotoxicity, mutagenicity, and chemoresistance of certain tumors. REV3L expression was found to be downregulated in the colon, lung, gastric, and renal cancer tissues as compared to adjacent tissues, whereas it was found to be upregulated in human glioma tissues.
Functions of REV3L
REV3L has been shown to increase cancer cell viability, especially after a cisplatin-induced injury. The inhibition of REV3L sensitized lung cancer H1299 cells to cisplatin treatment. Thus, REV3L may be a novel target for the chemotherapy of NSCLC. It was found to contain both functional nuclear and mitochondrial localization signals and to associate with POLγ in mitochondria. REV3L maintains genomic integrity by inserting a replacement nucleotide into the opposite DNA admixture, which increases mutation rates and contributes to cancer. REV3L suppressed the focus formation suggesting a tumor-suppressor role. REV3L was also established to be necessary for the proliferation of mouse embryonic fibroblasts, and inhibition of REV3L expression resulted in a pronounced growth arrest in Burkitt lymphoma, lung, breast, mesothelioma, and colon cancer cells.
Expression of REV3L in Diseases
Upregulation of REV3L markedly attenuated cisplatin-induced apoptosis of the mitochondrial apoptotic pathway. Down-regulating REV3L expression significantly enhanced the sensitivity of glioma cells to cisplatin. REV3L produces chemotherapy resistance to cisplatin by regulating cell cycle and apoptosis and may be a potential target for cervical cancer treatment. Depletion of REV3L suppressed cell proliferation and colony formation of cervical cancer cells, and the overexpression of REV3L promoted cell proliferation and colony formation of cervical cancer cells. As for chemotherapy resistance, upregulation of REV3L was previously demonstrated to serve a crucial role in many cancer types, including non-small cell lung cancer (NSCLC), through regulation of DNA repair. Overexpression of REV3L may accumulate genetic damages that are involved in the tumorigenesis and progression of esophageal squamous cell carcinoma (ESCC). The absence of REV3L (also known as REV3 in vertebrates) shows an increased sensitivity to exogenous injury. For example, REV3-null mouse-derived embryonic fibroblasts are more sensitive to UV- and γ-irradiation with increased chromosomal abnormalities. REV3L defects may lead to random ablation of cell lineages during embryonic development. The disruption of REV3L caused mid-gestation embryonic lethality.
Fig.1 Disruption of REV3L function prevents cell proliferation. (Lange, 2012)
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Reference
- Lange, S.S.; et al. DNA polymerase zeta is required for the proliferation of normal mammalian cells. Nucleic acids research. 2012, 40(10): 4473-4482.
