Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nucleotide excision repair (NER) is a versatile DNA repair pathway that eliminates various helix-distorting base lesions such as ultraviolet (UV)-induced photolesions. Several recessive human disorders, such as xeroderma pigmentosum (XP), are caused by hereditary defects in NER, implying that the pathway plays critical roles in suppressing diverse pathogenic processes, including carcinogenesis. In general, discrimination of lesion sites from intact DNA, which is present in vast excess, is a key determinant of the overall efficiency of DNA repair. In mammalian cells, global genomic NER lesion recognition is initiated by the XPC protein complex, which achieves broad DNA-binding specificity by sensing destabilized base pairs rather than lesions per se. To avert unnecessary incisions at lesion-free sites, and thereby ensure the fidelity of the repair system, transcription factor IIH and the XPA protein then verify the presence of relevant lesions at suspicious sites bound by XPC. In the case of UV-induced photolesions, a specialized lesion sensor called UV-damaged DNA-binding protein (UV-DDB) contributes to efficient lesion recognition and the recruitment of XPC to lesion sites. The ubiquitin-proteasome system plays a crucial role in the handoff of lesions from UV-DDB to XPC and the subsequent NER process. In addition, recognition of lesions targeted by global genomic NER is intricately regulated by higher-order chromatin structures, which play distinct roles depending on the type of lesion.
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PMID:Mechanism and regulation of DNA damage recognition in mammalian nucleotide excision repair. 3162 84

Base excision repair, which is initiated by the DNA N-glycosylase proteins, is the frontline for repairing potentially mutagenic DNA base damage. Several base excision repair genes are deregulated in cancer and affect cellular outcomes to chemotherapy and carcinogenesis. Endonuclease VIII-like 3 (NEIL3) is a DNA glycosylase protein that is involved in oxidative and interstrand crosslink DNA damage repair. Our previous work has showed that NEIL3 is required to maintain replication fork integrity. It is unknown whether NEIL3 overexpression could contribute to cancer phenotypes, and its prognostic value and use as potential drug target remain unexplored. Our analysis of cancer genomics data sets reveals that NEIL3 frequently undergoes overexpression in several cancers. Furthermore, patients who exhibited NEIL3 overexpression with pancreatic adenocarcinoma, lung adenocarcinoma, lower grade glioma, kidney renal clear cell carcinoma, and kidney papillary cell carcinoma had worse overall survival. Importantly, NEIL3 overexpressed tumors accumulate mutation and chromosomal variations. Furthermore, NEIL3 overexpressed tumors exhibit simultaneous overexpression of homologous recombination genes (BRCA1/2) and mismatch repair genes (MSH2/MSH6). However, NEIL3 overexpression is negatively correlated with tumor overexpressing nucleotide excision repair genes (XPA, XPC, ERCC1/2). Our results suggest that NEIL3 might be a potential prognosis marker for high-risk patients, and/or an attractive therapeutic target for selected cancers.
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PMID:Overexpression of NEIL3 associated with altered genome and poor survival in selected types of human cancer. 3236 78


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