REV1 promotes lung tumorigenesis by activating the Rad18/SERTAD2 axis

Chen, Yunshang; Jie, Xiaohua; Xing, Biyuan; Wu, Zilong; Yang, Xuezhou; Rao, Xinrui; Xu, Yingzhuo; Zhou, Dong; Dong, Xin; Zhang, Tao; Yang, Kunyu; Li, Zhenyu; Wu, Gang

doi:10.1038/s41419-022-04567-5

Cited by 9 publications

(15 citation statements)

References 35 publications

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“…Unlike other DNA repair pathways which are lost in cancer, RAD18 and DNA damage tolerance factors are often retained, supporting their role as fail-safe mechanisms for tumor cell survival. Indeed, multiple reports connect RAD18 and downstream TLS factors to tolerance of oncogene-induced replication stress, overexpression of RAD18 is also associated with increased survival, chemoresistance and cancer progression in various types of cancer [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

RAD18 opposes transcription-associated genome instability through FANCD2 recruitment

et al. 2022

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DNA replication is a vulnerable time for genome stability maintenance. Intrinsic stressors, as well as oncogenic stress, can challenge replication by fostering conflicts with transcription and stabilizing DNA:RNA hybrids. RAD18 is an E3 ubiquitin ligase for PCNA that is involved in coordinating DNA damage tolerance pathways to preserve genome stability during replication. In this study, we show that RAD18 deficient cells have higher levels of transcription-replication conflicts and accumulate DNA:RNA hybrids that induce DNA double strand breaks and replication stress. We find that these effects are driven in part by failure to recruit the Fanconi Anemia protein FANCD2 at difficult to replicate and R-loop prone genomic sites. FANCD2 activation caused by splicing inhibition or aphidicolin treatment is critically dependent on RAD18 activity. Thus, we highlight a RAD18-dependent pathway promoting FANCD2-mediated suppression of R-loops and transcription-replication conflicts.

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Section: Introductionmentioning

confidence: 99%

RAD18 opposes transcription-associated genome instability through FANCD2 recruitment

et al. 2022

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“…We purchased a lung adenocarcinoma tissues microarray composed of lung adenocarcinoma tissues and the paired adjacent normal tissues from Outdo Biotech. Immunohistochemical (IHC) staining was performed as described previously 24 . All ‐IHC images were scored one‐four and zero‐three based on the proportion of the area of positive staining cells in the total area of each field and the intensity of positive staining, respectively.…”

Section: Methodsmentioning

confidence: 99%

Targeting diacylglycerol kinase α impairs lung tumorigenesis by inhibiting cyclin D3

et al. 2023

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Background Diacylglycerol kinase α (DGKA) is the first member discovered from the diacylglycerol kinase family, and it has been linked to the progression of various types of tumors. However, it is unclear whether DGKA is linked to the development of lung cancer. Methods We investigated the levels of DGKA in the lung cancer tissues. Cell growth assay, colony formation assay and EdU assay were used to examine the effects of DGKA‐targeted siRNAs/shRNAs/drugs on the proliferation of lung cancer cells in vitro. Xenograft mouse model was used to investigate the role of DGKA inhibitor ritanserin on the proliferation of lung cancer cells in vivo. The downstream target of DGKA in lung tumorigenesis was identified by RNA sequencing. Results DGKA is upregulated in the lung cancer cells. Functional assays and xenograft mouse model indicated that the proliferation ability of lung cancer cells was impaired after inhibiting DGKA. And cyclin D3(CCND3) is the downstream target of DGKA promoting lung cancer. Conclusions Our study demonstrated that DGKA promotes lung tumorigenesis by regulating the CCND3 expression and hence it can be considered as a potential molecular biomarker to evaluate the prognosis of lung cancer patients. What's more, we also demonstrated the efficacy of ritanserin as a promising new medication for treating lung cancer.

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“…Inhibition of TLS by a small molecule, JH-RE-06 (which targets REV1) reduces survival of several cancer cell lines even in absence of an external stress ( 124 ). JH-RE-06 also suppresses growth of A549 and H1299 lung cancer cells grown as xenografts in vivo ( 155 ). Further consistent with a role for TLS in sustaining tumors, RAD18 overexpression elevates colonization of esophageal cancer cells in the mice lung ( 156 ), while RAD18-deficient TNBC xenografts show reduced tumor volume ( 157 ).…”

Section: Evidence That Tls Polymerases Contribute To Cancermentioning

confidence: 99%

“…Orthotopic injection of esophageal cancer cells overexpressing RAD18 increases colonization ( 156 ), while RAD18-deficient TNBC cell xenografts show reduced tumor growth ( 157 ). TLS inhibition by the REV1 inhibitor JH-RE-06 decreases colonization of lung cancer cells in mice ( 155 ). Therefore, studies with orthotopically-implanted cells support a role for TLS in tumor growth and as a cancer target.…”

Section: Evidence That Tls Polymerases Contribute To Cancermentioning

confidence: 99%

“…Overexpression of REV1 is strongly correlated with reduced survival probability of prostate cancer patients ( 195 , 196 , 197 ). Similarly, expression of REV1 is significantly upregulated in lung tumors compared with matched adjacent tissues, and such upregulation is associated with poor prognosis ( 155 ). Suppression of REV1 or REV3L not only sensitizes drug-resistant cancers to cisplatin, but also prevents acquisition of drug resistance in murine tumor models ( 198 , 199 ).…”

Section: How Does Tls Affect Response To Cancer Therapy?mentioning

confidence: 99%

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Roles of trans-lesion synthesis (TLS) DNA polymerases in tumorigenesis and cancer therapy

et al. 2023

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DNA damage tolerance and mutagenesis are hallmarks and enabling characteristics of neoplastic cells that drive tumorigenesis and allow cancer cells to resist therapy. The ‘Y-family’ trans-lesion synthesis (TLS) DNA polymerases enable cells to replicate damaged genomes, thereby conferring DNA damage tolerance. Moreover, Y-family DNA polymerases are inherently error-prone and cause mutations. Therefore, TLS DNA polymerases are potential mediators of important tumorigenic phenotypes. The skin cancer-propensity syndrome xeroderma pigmentosum-variant (XPV) results from defects in the Y-family DNA Polymerase Pol eta (Polη) and compensatory deployment of alternative inappropriate DNA polymerases. However, the extent to which dysregulated TLS contributes to the underlying etiology of other human cancers is unclear. Here we consider the broad impact of TLS polymerases on tumorigenesis and cancer therapy. We survey the ways in which TLS DNA polymerases are pathologically altered in cancer. We summarize evidence that TLS polymerases shape cancer genomes, and review studies implicating dysregulated TLS as a driver of carcinogenesis. Because many cancer treatment regimens comprise DNA-damaging agents, pharmacological inhibition of TLS is an attractive strategy for sensitizing tumors to genotoxic therapies. Therefore, we discuss the pharmacological tractability of the TLS pathway and summarize recent progress on development of TLS inhibitors for therapeutic purposes.

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REV1 promotes lung tumorigenesis by activating the Rad18/SERTAD2 axis

Cited by 9 publications

References 35 publications

RAD18 opposes transcription-associated genome instability through FANCD2 recruitment

RAD18 opposes transcription-associated genome instability through FANCD2 recruitment

Targeting diacylglycerol kinase α impairs lung tumorigenesis by inhibiting cyclin D3

Roles of trans-lesion synthesis (TLS) DNA polymerases in tumorigenesis and cancer therapy

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