Biomarkers of Toxicant Susceptibility
Anthony P. DeCaprio in Toxicologic Biomarkers, 2006
XPD/ERCC2 (excision repair cross-complementing) is involved in the NER pathway (29), which recognizes and repairs a wide range of structurally unrelated lesions such as bulky adducts and thymidine dimers. The XPD protein is an evolutionarily conserved helicase, a subunit of transcription factor IIH (TFIIH), that is essential for transcription and NER. Recently, the entire coding region of the DNA repair gene XPD/ERCC2 was resequenced in 12 normal individuals, and six polymorphic variants were described (30). Rare XPD mutations, which prevent interaction with p44, another subunit of TFIIH, and reduce its helicase activity result in three distinct clinical genetic diseases: XP, trichothiodystrophy, and XP combined with Cockayne sydrome. The functional significance of these newly identified XPD variants is not known. Many XPD polymorphisms are identified, e.g., C22541A at codon 156 of exon 6, at codon 199 (Ile→Met), at codon 312 (Asp→Asn), and A35931C at codon 751 of exon 23 (Lys→Gln). Allele frequencies are higher than 25% in sample populations from North America, England, and Italy, but homozygous alleles are very rare. XPD-Lys751Gln polymorphism, a conservative substitution, is associated with reduced in vitro repair of X-ray-induced DNA damage.
Bladder Cancer
Pat Price, Karol Sikora in Treatment of Cancer, 2020
Fifty-eight significantly mutated genes have been identified; the main features are summarized in Figure 13.1. TP53 and cell cycle genes were mutated in 89% of tumors including TP53 in 48%, MDM2 over-expression in 25%, and RB mutations 17%, CDKN2a mutation/deletion 22%, CDKN1A in 11%. RAS/PI3K pathway was also frequently mutated (in ~70%). An unexpected major feature has been the frequency of chromatin remodeling genes with ten genes mutated at >5% frequency and occurring in over 50% of tumors, the significance of which is unclear. DNA repair genes are also found to be mutated in around 16% cases including ATM (14%), ERCC2 (9%), and RAD51 (2%). FGFR2/3 mutations have reported to occur in 15–20% of cases with the frequency being higher in lower-stage lower-grade tumors.
Xeroderma Pigmentosum
Dongyou Liu in Handbook of Tumor Syndromes, 2020
Homozygous or compound heterozygous mutations in the XPA, ERCC3, XPC, ERCC2, DDB2, ERCC4, and ERCC5 as well as POLH genes produce loss-of-function proteins and compromise the efficiency of the NER pathway to remove and repair DNA lesions caused by UV radiation, leading to the development of hereditary disorders XP, Cockayne syndrome (CS), and trichothiodystrophy (TTD). While XP patients show an increased risk for skin cancer, CS (due to CSA and CSB mutations) and trichothiodystrophy (due to TTDA mutation) patients do not develop skin cancer. However, XP-CS complex patients (due to loss of function ERCC3/XPB, ERCC2/XPD, ERCC4/XPF, ERCC5/XPG) may still have skin cancer similar to XP patients (Table 50.1) [8].
Association of XRCC1 and XPD functional gene variants with nicotine dependence and/or schizophrenia: a case-control study and in silico analysis
Published in Psychiatry and Clinical Psychopharmacology, 2019
S. Pehlivan, N. Aydin, A. F. Nursal, M. A. Uysal, M. Pehlivan, A. Tekcan, F. K. Yavuz, U. Sever, H. Yavuzlar, S. Kurnaz, S. Uysal, P. C. Aydin
X-ray repair cross-complementing group 1 (XRCC1) gene, found at chromosome 19q13.2, is a major component of base excision repair (BER) and is necessary for genetic stability [6]. Xeroderma pigmentosum complementation group D (XPD) is among the crucial DNA repair genes [7]. This is also called as the excision repair cross-complementing complementation group 2 (ERCC2) gene and located in chromosome 19q13.2–13.3 and codes for an evolutionally conserved helicase which plays a key role in transcription and nucleotide excision repair (NER) [7]. Genetic variation in DNA repair genes can have an impact on the activity of DNA repair enzymes, thus modifying the DNA repair ability. This study aimed to find out whether functional SNP variants in the XRCC1 Arg399Gln (rs25487), XPD Lys751Gln (rs13181) variants play any role in both ND and Sch + ND etiopathogenesis in a Turkish population, which was followed up with an in silico analysis approach.
Genetic variations as molecular diagnostic factors for idiopathic male infertility: current knowledge and future perspectives
Published in Expert Review of Molecular Diagnostics, 2021
Mohammad Karimian, Leila Parvaresh, Mohaddeseh Behjati
ERCC2 is part of the nucleotide excision repair (NER) pathway, which is an integral part of the basal transcription factor BTF2/TFIIH [71]. Reports of cDNA microarrays have shown that ERCC2 gene expression in azoospermic testes is significantly upregulated compared to normal ones [71]. ERCC1 is another essential component of the NER pathway, where it acts in a complex with XPF to repair DNA damage [72]. Ercc1-deficient testes show increased levels of DSBs, oxidative DNA damage, and apoptosis in their male germ cells [72]. In a case–control study following by a meta-analysis, Singh et al., 2019 reported that ERCC2 751A>C SNP is associated with male infertility. However, they did not find any significant association between ERCC2 751A>C, and ERCC1 C>A 3′UTR polymorphisms and male infertility in their meta-analysis [73].
Novel targeted strategies to overcome resistance in small-cell lung cancer: focus on PARP inhibitors and rovalpituzumab tesirine
Published in Expert Review of Anticancer Therapy, 2019
Robin Van Den Borg, Alessandro Leonetti, Marcello Tiseo, Elisa Giovannetti, Godefridus J. Peters
The cisplatin-induced DNA damage mainly activates cell cycle checkpoints. This event induces a transient cellular S-phase arrest, and later a durable G2/M-phase arrest, caused by the inhibition of Cdc2-cyclin A or B kinases [27]. Normally, cell cycle arrest is associated with an inhibitory effect on the cytotoxicity of cisplatin as it is needed to enable nucleotide excision repair (NER) complex to eliminate the formed adducts and promote cell survival. NER can indeed recognize the DNA adduct via XPA protein, which leads to the recruitment of proteins to form a complex. ERCC2 and ERCC3 helicases dissociate the two DNA strands, after which ERCC4 and ERCC5 endonucleases can cleave the damaged strand at 3ʹ and 5ʹ sides. This enables POL-δ and POL-ε to resynthesize the excised strand. Ligase III can next re-ligate the newly synthesized DNA to the main DNA chain [23]. When cisplatin induces extensive damage to the DNA and the repair via NER is incomplete, apoptosis will occur [28].
Related Knowledge Centers
- Cockayne Syndrome
- Exon
- Intron
- Nucleotide Excision Repair
- Amino Acid
- Xeroderma Pigmentosum
- Trichothiodystrophy
- Xpb
- Initiation Factor
- Transcription Factor II H