Diverse roles of RAD18 and Y-family DNA polymerases in tumorigenesis

Yang, Yang; Gao, Yanzhe; Zlatanou, Anastasia; Tateishi, Seiichiro; Yurchenko, Vyacheslav; Rogozin, Igor B.; Vaziri, Cyrus

doi:10.1080/15384101.2018.1456296

Cited by 39 publications

(33 citation statements)

References 108 publications

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“…There are 95 Rad18 variants distinguishing B6J from D2J https://www.sanger.ac.uk), including five, 3' UTR variants, 25 intronic nmd variants, and one 7 Kb structural variant (deletion) (see Supplementary Table 1 for high impact variants). Rad18 dysfunction can lead to mutagenesis, carcinogenesis, and tumorigenesis (Yang et al 2018). Expression QTLs from several brain tissues were linked to Rad18 expression which, in turn, were correlated with several traits related to BW, metabolism, emotional, and substance use disorder traits (Supplementary Figure 4).…”

Section: Discussionmentioning

confidence: 99%

Systems genetic analysis of binge-like eating in a C57BL/6J x DBA/2J-F2 cross

Yao

Babbs

Kelliher

et al. 2020

Preprint

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Word count in abstract: 247 Word count in main text: 4410 ACKNOWLEDGEMENTS This work was funded by R21DA038738 (C.D.B.), R01DA039168 (C.D.B.), and R01CA221260 (M.I.D., C.D.B.) ABSTRACTObjective. Binge eating is a heritable quantitative trait associated with eating disorders (ED) and refers to the rapid consumption of a large quantity of energy-dense food that is associated with loss of control, anxiety, and depression. Binge Eating Disorder is the most common ED in adults in the US; however, the genetic basis is unknown. We previously identified robust mouse inbred strain differences between C57BL/6J and DBA/2J in binge-like eating (BLE) of sweetened palatable food (PF) in an intermittent access, conditioned place preference paradigm. Methods.To map the genetic basis of BLE, we phenotyped and genotyped 128 C57BL/6J x DBA/2J-F2 mice.Results. We identified a quantitative trait locus (QTL) on chromosome 13 influencing progressive changes in body weight across training days (LOD = 5.5; 26-39 cM). We also identified two sex-combined QTLs influencing PF intake on chromosome 5 (LOD = 5.6; 1.5-LOD interval = 21-28 cM) and 6 (LOD = 5.3; 1.5-LOD interval = 50-59 cM). Furthermore, sex-specific analyses revealed that the chromosome 6 locus was driven by males (1.5-LOD interval: 52-59 cM) and identified a female-selective QTL for BLE on chromosome 18 (LOD = 4.1; 1.5-LOD interval: 23-35 cM). Systems genetic analysis of the chromosome 6 locus for BLE using GeneNetwork legacy trait datasets from BXD recombinant inbred strains identified Adipor2 and Plxnd1 as two positional, functional, biological candidate genes.Discussion. We identified genetic loci influencing BLE. Future studies will phenotype BXD recombinant inbred strains to fine map loci and support candidate gene nomination and validation.

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Section: Discussionmentioning

confidence: 99%

Systems genetic analysis of binge-like eating in a C57BL/6J x DBA/2J-F2 cross

Yao

Babbs

Kelliher

et al. 2020

Preprint

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“…This overexpression likely results in the increased monoubiquitination of PCNA, inappropriately activating TLS to drive cancer mutagenesis. Rad18 overexpression is commonly coupled with overexpression of its binding partner Melanoma Antigen-A4 (MAGE-A4) [ 91 ]. MAGE-A4 overexpression stabilizes Rad18 by protecting it from ubiquitin-mediated degradation, allowing for its continued over-activation in cancer cells [ 92 ].…”

Section: Dna Damage Bypass and Cancermentioning

confidence: 99%

Ubiquitin and Ubiquitin-Like Proteins Are Essential Regulators of DNA Damage Bypass

Wilkinson

Mnuskin

Ashton

et al. 2020

Cancers

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Many endogenous and exogenous factors can induce genomic instability in human cells, in the form of DNA damage and mutations, that predispose them to cancer development. Normal cells rely on DNA damage bypass pathways such as translesion synthesis (TLS) and template switching (TS) to replicate past lesions that might otherwise result in prolonged replication stress and lethal double-strand breaks (DSBs). However, due to the lower fidelity of the specialized polymerases involved in TLS, the activation and suppression of these pathways must be tightly regulated by post-translational modifications such as ubiquitination in order to limit the risk of mutagenesis. Many cancer cells rely on the deregulation of DNA damage bypass to promote carcinogenesis and tumor formation, often giving them heightened resistance to DNA damage from chemotherapeutic agents. In this review, we discuss the key functions of ubiquitin and ubiquitin-like proteins in regulating DNA damage bypass in human cells, and highlight ways in which these processes are both deregulated in cancer progression and might be targeted in cancer therapy.

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“…The E3 ubiquitin-protein ligase RAD18 plays a vital role in DNA damage bypass and post-replication repair (PRR) through the promotion of proliferating cell nuclear antigen (PCNA) mono-ubiquitination at stalled replication forks (3). Recent studies have shown that high expression of RAD18 in cancerous tissues is associated with cancer metastasis and tumor progression in a variety of cancers (4)(5)(6). In melanoma, studies demonstrated that RAD18 participates in the regulation of cell proliferation, and its high expression is associated with poor five-year patient survival (7).…”

Section: Introductionmentioning

confidence: 99%

RAD18 promotes colorectal cancer metastasis by activating the epithelial‑mesenchymal transition pathway

Gao

et al. 2020

Oncol Rep

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RAD18 is an E3 ubiquitin-protein ligase that has a role in carcinogenesis and tumor progression owing to its involvement in error-prone replication. Despite its significance, the function of RAD18 has not been fully examined in colorectal cancer (CRC). In the present research, by collecting clinical samples and conducting immunohistochemical staining, we found that RAD18 expression was significantly increased in the CRC tissue compared with that noted in the adjacent non-cancerous normal tissues and that high expression of RAD18 was associated with lymph node metastasis and poor prognosis in CRC patients. In vitro, as determined by cell transfection, scratch, and Transwell experiments, it was also demonstrated that RAD18 increased the invasiveness and migration capacity of CRC cells (HCT116, DLD-1, SW480). The signaling pathway was analyzed by western blotting and the clinical data were analyzed by immunohistochemical staining and RT-PCR, indicating that the process of epithelial-mesenchymal transition (EMT) may be involved in RAD18-mediated migration and invasion of CRC cells. All of the above data indicate that RAD18 is a novel prognostic biomarker that may become a potential therapeutic target for CRC in the future.

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Diverse roles of RAD18 and Y-family DNA polymerases in tumorigenesis

Cited by 39 publications

References 108 publications

Systems genetic analysis of binge-like eating in a C57BL/6J x DBA/2J-F2 cross

Systems genetic analysis of binge-like eating in a C57BL/6J x DBA/2J-F2 cross

Ubiquitin and Ubiquitin-Like Proteins Are Essential Regulators of DNA Damage Bypass

RAD18 promotes colorectal cancer metastasis by activating the epithelial‑mesenchymal transition pathway

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