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Xeroderma Pigmentosum
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
As the most important repair pathway in mammals for removal of UV light-induced lesions (including cyclobutane pyrimidine dimers [CPD], 6–4 photoproducts, and helix-distorting chemical adducts), the NER pathway consists of two subpathways, i.e., global genome repair (GGR) and transcription-coupled repair (TCR). The GGR subpathway is a slow process that utilizes XPC and DDB2/XPE to identify/mark DNA injuries/lesions anywhere in the genome. The TCR subpathway relies on CSA/ERCC8 and CSB/ERCC6 to detect DNA damages occurring at transcribed strands of active genes that block RNA polymerase II transcription/elongation and that are inefficiently recognized by the GGR subpathway, allowing rapid resumption of the vital process of RNA synthesis. Once detected, the DNA lesions are removed and repaired by the multi-subunit TFIIH complex (transcription factor II H complex, consisting of XPA, ERCC3/XPB, ERCC2/XPD, ERCC4/XPF, ERCC5/XPG, and other molecules) in the NER pathway. Specifically, XPB and XPD helicases in the TFIIH complex open the DNA double helix around the lesion, and XPA and replication protein A (RPA) help assemble and properly orientate XPF and XPG endonucleases, which excise the damaged strand around the lesion (5′ and 3′, respectively), leaving an excised stretch of ∼30 nucleotides for DNA polymerase δ/ε and auxiliary factors to fill, and ligase 1 to seal (Figure 50.1) [1,3,7].
Head and Neck Cancers
Published in Peter G. Shields, Cancer Risk Assessment, 2005
Qingyi Wei, Hongbing Shen, Margaret R. Spitz, Erich M. Sturgis, Peter G. Shields
Polymorphisms of DNA repair genes may also contribute to variations in DRC. Clearly, functional (phenotypic) studies of DNA repair in individuals with various DNA repair genotypes are needed. However, it will be difficult to detect subtle differences in DRC in such studies due to a single polymorphism of a single gene in a very complex pathway. Recently, the entire coding regions of the following DNA repair genes on chromosome 19 were resequenced in 12 normal individuals (132): three NER genes (ERCC1, XPD/ERCC2, and XPF/ERCC4), one HRR gene (XRCC3), and one BER gene (XRCC1). Among these, 7 variants of ERCC1, 17 variants of XPD/ERCC2, 6 variants of XPF/ERCC4, 4 variants of XRCC3, and 12 variants of XRCC1 were identified. Of these variants, 4 of XPD/ERCC2,3of XRCC1,1of XRCC3 and 1 of XPF/ERCC4 result in an amino acid sequence change. Later, another 6 variants of XPF/ERCC4 were identified in 38 individuals (133), 2 variants of XPA (chromosome 9), and 2 variants of XPB/ERCC3 (chromosome 2) were identified in 35 individuals, and 2 variants of XPC (chromosome 3) (134) and 3 variants of XPG/ERCC5 (chromosome 13) (135) were also identified. Although the significance of these variants is largely unknown, the implication is those that cause amino acid substitutions may have an impact on the function of the proteins and therefore on the efficiency of DNA repair. Variants that do not cause an amino acid change may also have an impact on the DNA repair function through altered splicing, mRNA instability, or linkage with other genetic changes. Therefore, knowing the impact of these polymorphisms on disease risk is important to ultimately understanding their functional relevance.
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].
Genetic risk factors for cancer-related cognitive impairment: a systematic review
Published in Acta Oncologica, 2019
Cecilie D. R. Buskbjerg, Ali Amidi, Ditte Demontis, Eva R. Nissen, Robert Zachariae
One cross-sectional [30] and one longitudinal follow-up study [23] investigated associations of four DNA repair genes and five oxidative stress genes, with CRCI in BC patients recruited from the same parent study and scheduled for treatment with AI and/or CT. Neuropsychological test scores were combined into eight cognitive factors. Prior to adjuvant treatment, each cognitive factor was significantly associated with one or more DNA repair or oxidative stress gene SNPs. A multi-polymorphism genetic risk score (GRS) was calculated for each cognitive factor to evaluate the collective effect of possessing multiple identified risk SNPs. A lower GRS was taken to indicate greater risk and a higher GRS indicated lower risk of cognitive impairment. Results revealed that each GRS was significantly associated with its respective cognitive factor, indicating that the higher the genetic protection, the better the cognitive performance [30]. In the follow-up study [23], group-based trajectory modeling was used to investigate trajectories of three cognitive factors, i.e., executive functioning, concentration and visual working memory. Three distinct executive functioning trajectory subgroups were identified: low pretreatment performance that remained low (low), pretreatment performance slightly below the norm that improved linearly (moderate), and high performance that improved and then declined (high). Results showed that the minor allele of SNPs in three DNA repair genes (PARP1 (rs2271347), ERCC3 (rs4150402) and ERCC5 (rs751492)) increased the odds of belonging to the executive functioning low trajectory subgroup. Similar findings of increased odds of belonging to various trajectory subgroups were found for various DNA repair and oxidative stress genes in the domains of concentration and visual working memory (Table 1). Effect sizes varied considerably with the lowest risk seen for an executive functioning trajectory subgroup (OR = 0.29, 95% CI: 0.10–0.82) and the largest risk seen for a concentration trajectory subgroup (OR = 8.26, 95% CI: 1.34–50.98). Taken together, these results provide preliminary evidence that genetic variation in DNA repair and oxidative stress genes may impart differential risks for trajectories of cognitive functioning during treatment.