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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].
CDK Inhibitors in Leukemia and Lymphoma
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Flavopiridol very potently represses transcription (IC50 < 10 nM) in vitro by blocking transition into productive elongation mediated by RNAPII, which is controlled by P-TEFb (cyclin T-CDK9) (24). Flavopiridol inhibits CTD kinase activity of RNAPII with a Ki value of 3 nM, a concentration significantly lower than that required for the inhibition of most other CDKs (e.g., CDKs 1, 2, and 4 with Ki values between 40 and 70 nM). Furthermore, unlike the inhibition of other CDKs, inhibition of CDK9 by flavopiridol is noncompetitive with respect to ATP. In cells, flavopiridol inhibits transcription at concentrations far lower than those required to inhibit CDK1 and CDK2, even in the presence of the physiologic concentration of ATP. Another potential target for transcriptional repression by flavopiridol is CDK7 (catalytic subunit of TFIIH). However, CDK7 inhibition requires higher concentrations of flavopiridol than those necessary for the inhibition of CDK9 (23). Therefore, inhibition of transcription by flavopiridol primarily stems from the direct inhibition of CDK9.
Cockayne Syndrome and the Aging Process
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
ERCC8 gene: (excision repair 8, cross-complementing protein): its cytogenetic location is 5q12.1. The protein is a polypeptide of 396 amino acids with a molecular weight of 44 kDa. The function of this gene product is similar to the one of the ERCC6 gene. It has domains with repeated sequences, a WD40, that joins the ERCC6 protein and forms a complex and also joins with the p44 subunit from TFIIH from the RNA polymerase (Kashiyama et al., 2013).
The roles of TPL in hematological malignancies
Published in Hematology, 2023
Tingyun Xu, Yiwei Zhu, Shuaishuai Ge, Song-Bai Liu
CD26 is a type II glycoprotein that has been used as a poor prognostic factor, and CD26-positive cells have been found to be highly expressed in various hematologic tumors [107–109]. Humanized anti-CD26 monoclonal antibody (YS110) has been coupled to TR1, a modified version of TPL at the sulfhydryl (SH) group, to produce an antibody–drug conjugate Y-TR1. Y-TR1 binds to CD26 on the cell surface and can cause cell death through immune-mediated cytotoxicity [110, 111]. Y-TR1 significantly inhibits the proliferation of CD26-positive tumor cells without affecting CD26-negative cells. YS110 can be internalized to the nucleus to inhibit cell proliferation by suppressing the transcription of POLR2A, a subunit of RNA polymerase II. Y-TR1 inhibits cell proliferation by inhibiting general transcription factor IIH (TFIIH), which is required for the transcription of RNA polymerase II (Pol II) [111, 112].
A patent review of cyclin-dependent kinase 7 (CDK7) inhibitors (2018-2022)
Published in Expert Opinion on Therapeutic Patents, 2023
Markéta Kovalová, Joseph Peter Baraka, Václav Mik, Radek Jorda, Lei Luo, Hao Shao, Vladimír Kryštof
Cyclin dependent kinases (CDKs) constitute a family of serine/threonine protein kinases that form active complexes with corresponding cyclins to regulate cell cycle transitions and transcription [1]. CDK7 associates with cyclin H and MAT1 to form the CDK-activating kinase (CAK) complex, directing cell cycle transitions by phosphorylating the T-loop of cell cycle CDKs, such as CDK1, 2, 4 and 6 [2,3]. CDK7 is also a component of the general transcription factor IIH (TFIIH), facilitating transcription initiation by phosphorylating the C-terminal domain (CTD) heptapeptide repeats of RNA polymerase II (RNAP II) at Ser5 and Ser7 residues [4,5]. In addition, CDK7 phosphorylates CDK9, a component of positive transcription elongation factor b (P-TEFb), which in turn, phosphorylates the Ser2 residue of the RNAP II CTD to allow productive transcription elongation [6].
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].