REV3L, also known as Protein reversion less 3-like, encodes the catalytic subunit of error-prone translesion synthesis polymerase ζ. This polymerase is involved in the DNA damage tolerance mechanism of translesion synthesis (TLS), which allows DNA replication to proceed past DNA lesions. TLS is crucial for maintaining genome stability in the face of DNA damage [1,2,3,4,5,6].

In non-small cell lung cancer (NSCLC), certain single nucleotide variants in REV3L (rs1002481, rs462779, rs465646) are significantly associated with an increased risk of the disease under the recessive model, suggesting its potential as a genetic predisposition marker [1]. In NSCLC H1299 cells, cisplatin treatment induces REV3L expression. Overexpression of REV3L confers resistance to cisplatin, while knockdown sensitizes the cells, indicating it can be a novel target for NSCLC chemotherapy [2]. Similar roles in chemoresistance are seen in esophageal squamous cell carcinoma, gliomas, and cervical cancer. In esophageal squamous cell carcinoma, REV3L is upregulated, and its downregulation decreases cell proliferation, invasive capacity, and increases sensitivity to 5-fluorouracil [3]. In gliomas, REV3L overexpression attenuates cisplatin-induced apoptosis, and RNAi-mediated downregulation enhances cisplatin sensitivity [4]. In cervical cancer, suppression of REV3L enhances cisplatin sensitivity, while overexpression confers resistance [5]. A homozygous ultra-rare REV3L variant (T2753R) in a child is associated with developmental delay, hypotrophy, and dysmorphic features, and in yeast, an equivalent mutation shows dysfunction of TLS in the nucleus and instability of mitochondrial genetic information [6]. A c.9253-6T>C REV3L mutation in a myelodysplastic syndrome patient is associated with poor prognosis [7]. In NSCLC, circular RNA PRMT5 promotes cisplatin resistance via the miR-4458/REV3L axis [8]. MAD2L2 promotes replication fork protection and recovery in a REV3L-dependent manner [9].

In conclusion, REV3L is essential for translesion synthesis and genome stability. Its role in various cancers, such as NSCLC, esophageal squamous cell carcinoma, gliomas, and cervical cancer, highlights its significance in cancer development and chemoresistance. The discovery of its association with developmental disorders and myelodysplastic syndrome also broadens our understanding of its impact on human health. Studies on REV3L contribute to uncovering disease mechanisms and may provide new therapeutic targets.