Dataset Information

Genetic polymorphism (rs246079) of the DNA repair gene uracil N-glycosylase is associated with increased risk of cervical carcinoma in a Chinese population.

ABSTRACT: The aim of this case-control study was to clarify the relationship between uracil N-glycosylase (UNG) rs3219218 and rs246079 genotypes and risk of cervical squamous cell cancer (CSCC). Modified polymerase chain reaction-mismatch amplification (MA-PCR) was applied for genotyping UNG rs3219218 (A/G) and UNG rs246079 (A/G) polymorphisms in 400 CSCC, 400 cervical intraepithelial neoplasia (CIN) III, and 1200 normal controls. We observed no association between the UNG rs3219218 (A/G) polymorphism and risk of CIN III or CSCC. However, risk of CIN III (odds ratio [OR]?=?1.58) and CSCC (OR?=?2.08) was significantly increased in cases with the homozygous GG genotype of UNG rs246079. At the UNG rs246079 (A/G) locus, individuals with the G allele or G carrier (GG?+?AG) genotype were at higher risk for CIN III (OR?=?1.34) and CSCC (OR?=?1.55). In the high-risk HPV (HR-HPV) positive group, homozygous GG of the UNG rs246079 genotype was associated with significantly increased risk of CSCC (OR?=?2.37) and CIN III (OR?=?1.81). Meanwhile, the proportion of G allele was significantly increased in CIN III (49.2%, OR?=?1.33) and CSCC (52.5%, OR?=?1.50) groups. G allele or G carrier (GG?+?AG) genotype was identified as a high-risk factor in CSCC (OR?=?1.67) while in the CIN III group, no major differences were evident relative to the control group (OR?=?1.45). A particularly high level of enrichment grouping was evident according to the number of sexual partners in the CIN III (P?=?.036) and CSCC (P?=?.001) groups. Our data clearly suggest an association between UNG rs246079 (A/G) and CSCC carcinogenesis, supporting the potential application of this polymorphism as a genetic biomarker for early prediction of cervical carcinoma.

SUBMITTER: Ye F

PROVIDER: S-EPMC6319868 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Genetic polymorphism (rs246079) of the DNA repair gene uracil N-glycosylase is associated with increased risk of cervical carcinoma in a Chinese population.

Ye Feng F Wang Hanzhi H Liu Jia J Cheng Qi Q Chen Xiaojing X Chen Huaizeng H

Medicine 20181201 51

The aim of this case-control study was to clarify the relationship between uracil N-glycosylase (UNG) rs3219218 and rs246079 genotypes and risk of cervical squamous cell cancer (CSCC). Modified polymerase chain reaction-mismatch amplification (MA-PCR) was applied for genotyping UNG rs3219218 (A/G) and UNG rs246079 (A/G) polymorphisms in 400 CSCC, 400 cervical intraepithelial neoplasia (CIN) III, and 1200 normal controls. We observed no association between the UNG rs3219218 (A/G) polymorphism and ...[more]

PMID: 30572497

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Project description:HDAC inhibitors (HDACi) belong to a new group of chemotherapeutics that are increasingly used to treat B-cell-derived malignancies. Such malignancies regularly carry mutational signatures that conform to off-target induction of uracil by the AID/APOBEC family of cytidine deaminases, or downstream processing of uracil. . HDACi suppress thymidylate synthase increasing the cellular dUTP/dTTP ratio and leading to increased pressure on uracil repair machinery due to misincorporated uracil lesions. To investigate potential effect upon other enzymes involved in genomic uracil induction and processing, Jurkat (T-cell lymphoma) and SUDHL5 (B-cell lymphoma) cells were treated with pan-HDACi SAHA prior to SILAC based MS/MS investigation. HDACi treatment mediated significant differential expression of xx and xx proteins in Jurkat and SUDHL5, respectively, and had a substantial impact upon enzymes involved in in pyrimidine metabolism. Surprisingly, uracil N-glycosylase, UNG, was strongly downregulated by HDACi treatment. Further analysis in HEK and HeLa cells revealed that HDACis induce specific loss of the nuclear isoform UNG2 independent of transcription and cell-cycle alterations. More than 80% of UNG2 is degraded proteasomally after 24 hours treatment with SAHA, MS275, Valproate or Na-butyrate, indicating a universal ability of HDACis to mediate loss of UNG2. Targeted MS/MS analysis in HEK cells against a panel of proteins involved in DNA repair, translesion synthesis and nucleotide metabolism, revealed that UNG2 was the most pronounced differentially expressed among these after HDACi treatment. 48 hour treatment lead to a 30-40% increase in uracil lesions in the nuclear genome of HeLa and HEK cells and MS275 treatment in murine CH12F3 cell line mediated robust UNG2-loss accompanied by reduced class switch recombination. Furthermore, our analysis identified the PCNA-associated factor PAF15 among the downregulated proteins. PAF15 is overexpressed in many cancers and suppress TLS by inducing double monoubiquitinylation of PCNA and recruitment of the replicative polymerases. In summary, our findings demonstrate that HDAC inhibition affects the levels of proteins involved in DNA base excision repair, translesion synthesis and pyrimidine metabolism. These findings are important for a wide range of clinical applications of HDACi, such as in rheumatology, HIV-, and cancer treatment.

Dataset Information

Genetic polymorphism (rs246079) of the DNA repair gene uracil N-glycosylase is associated with increased risk of cervical carcinoma in a Chinese population.

Publications

Genetic polymorphism (rs246079) of the DNA repair gene uracil N-glycosylase is associated with increased risk of cervical carcinoma in a Chinese population.

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