DNA Damage: From Threat to Treatment

Carusillo, Antonio; Mussolino, Claudio

doi:10.3390/cells9071665

Cited by 138 publications

(118 citation statements)

References 142 publications

(160 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…DDR mechanisms can repair mutated genes during the early stage of cancer and hinder the development of tumors [23]. However, with the development of cancer, DDRs may cause tumor cells to develop resistance to cytotoxic drugs [24,25]. The occurrence and development of cancer are often accompanied by the inactivation of one or more DDR pathways; however, cancer cells are therefore more dependent on the remaining DDR pathways than normal cells [25].…”

Section: Discussionmentioning

confidence: 99%

Screening of DNA Damage Repair Genes Involved in the Prognosis of Triple-Negative Breast Cancer Patients Based on Bioinformatics

Wang

Chi

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: Triple-negative breast cancer (TNBC) is a special subtype of breast cancer with poor prognosis. DNA damage response (DDR) is one of the hallmarks of this cancer. However, the association of DDR genes with the prognosis of TNBC is still unclear.Methods: We identified differentially expressed genes (DEGs) between normal and TNBC samples from The Cancer Genome Atlas (TCGA). DDR genes were obtained from the Molecular Signatures Database (MSigDB) through six DDR gene sets. We then overlapped the DEGs with DDR genes. Based on univariate and LASSO Cox regression analyses, a prognostic model was constructed to predict overall survival (OS). Kaplan–Meier (K–M) analysis and receiver operating characteristic (ROC) curve were used to assess the performance of the prognostic model. Cox regression analysis was applied to identify independent prognostic factors in TNBC. The prognostic model was validated using an independent dataset. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed by using gene set enrichment analysis (GSEA). Single-sample gene set enrichment analysis (ssGSEA) was employed to estimate immune cells related to this prognostic model. Finally, we constructed a transcriptional factor (TF) network and a competing endogenous RNA (ceRNA) regulatory network.Results: 23 differentially expressed DDR genes were detected between TNBC and normal samples. The six-gene prognostic model we developed was shown to be related to OS in TNBC using univariate and LASSO Cox regression analyses. By drawing ROC curve and KM curve, we determined the effectiveness of the risk model. The prognostic value of the six-gene prognostic model was further validated using the GSE58812 dataset. The GSEA analysis indicated that the genes in the high-risk group were mainly correlated with leukocyte migration, cytokine interaction with cytokine receptors, oxidative phosphorylation, autoimmune diseases, and coagulation cascade. The mutation data revealed that the mutation frequency of the two groups was the same, while the mutated genes were different. The gene-TF regulatory network showed that Replication Factor C subunit 4 (RFC4) occupied the dominant position.Conclusion: We identified six gene markers related to DDR, which can predict prognosis and serve as an independent biomarker for TNBC patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Screening of DNA Damage Repair Genes Involved in the Prognosis of Triple-Negative Breast Cancer Patients Based on Bioinformatics

Wang

Chi

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Defects in the DNA damage response (DDR) contributes to the genomic instability, and consequently aids in cancer initiation and progression [19]. Understanding the factors involved in DDR offers targetable vulnerabilities relatively speci c to cancer cells, which may bring potential bene t to clinical management [20]. TRAIP, as a key regulator in DDR, exerts paradoxical activities in cancer progression.…”

Section: Discussionmentioning

confidence: 99%

TRAIP functions as an oncogene in hepatocellular carcinoma via Rb/EZH2/p21 signaling pathway

Luo¹,

Li²,

Zhang³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background The TRAF-interacting protein (TRAIP) has been identified as a master regulator of DNA damage and implicated in the progression of human cancers. Yet the underlying mechanism of TRAIP-mediated malignant phenotype remains unclear. Methods The expression of TRAIP in hepatocellular carcinoma (HCC) was examined by qRT-PCR, western blot and immunohistochemistry. The clinical significance of TRAIP was determined by Kaplan-Meier survival analyses. The biological function and the underlying mechanism of TRAIP in HCC progression were investigated, using cellular and molecular biological experiments.Results Here, we show that TRAIP is upregulated in HCC and functions as an oncogene via Rb/EZH2/p21 signaling. Overexpression of TRAIP, at both mRNA and protein levels, is correlated with more aggressive clinicopathological features, and unfavorable overall and disease-free survivals. In vitro experiments demonstrate that ectopic expression of TRAIP enhances, whereas knockdown of TRAIP attenuates HCC cell proliferation. Further data show that TRAIP interacts with SPAG5 in HCC cells, which results in the stabilization of TRAIP protein. TRAIP overexpression suppresses the expression of Rb, subsequently leading to the increase of EZH2 and decrease of p21. Re-expression of Rb and p21 significantly inhibits TRAIP-mediated cell growth. Conclusion Collectively, our findings suggest TRAIP exert oncogenic activity and have prognostic and therapeutic potential in HCC.

show abstract

“…Like other DNA damage repair proteins [ 10 ], SNM1A is a potential target for overcoming resistance to crosslinking agents in cancers [ 11 ]. Inhibitors reported to date are limited to o -phenanthroline [ 12 ], cephalosporins [ 13 ], and a modified nucleoside inhibitor [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Probing the Binding Requirements of Modified Nucleosides with the DNA Nuclease SNM1A

Dürr

McGouran

2021

Molecules

View full text Add to dashboard Cite

SNM1A is a nuclease that is implicated in DNA interstrand crosslink repair and, as such, its inhibition is of interest for overcoming resistance to chemotherapeutic crosslinking agents. However, the number and identity of the metal ion(s) in the active site of SNM1A are still unconfirmed, and only a limited number of inhibitors have been reported to date. Herein, we report the synthesis and evaluation of a family of malonate-based modified nucleosides to investigate the optimal positioning of metal-binding groups in nucleoside-derived inhibitors for SNM1A. These compounds include ester, carboxylate and hydroxamic acid malonate derivatives which were installed in the 5′-position or 3′-position of thymidine or as a linkage between two nucleosides. Evaluation as inhibitors of recombinant SNM1A showed that nine of the twelve compounds tested had an inhibitory effect at 1 mM concentration. The most potent compound contains a hydroxamic acid malonate group at the 5′-position. Overall, our studies advance the understanding of requirements for nucleoside-derived inhibitors for SNM1A and indicate that groups containing a negatively charged group in close proximity to a metal chelator, such as hydroxamic acid malonates, are promising structures in the design of inhibitors.

show abstract

DNA Damage: From Threat to Treatment

Cited by 138 publications

References 142 publications

Screening of DNA Damage Repair Genes Involved in the Prognosis of Triple-Negative Breast Cancer Patients Based on Bioinformatics

Screening of DNA Damage Repair Genes Involved in the Prognosis of Triple-Negative Breast Cancer Patients Based on Bioinformatics

TRAIP functions as an oncogene in hepatocellular carcinoma via Rb/EZH2/p21 signaling pathway

Probing the Binding Requirements of Modified Nucleosides with the DNA Nuclease SNM1A

Contact Info

Product

Resources

About