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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].
Biomarkers of Toxicant Susceptibility
Published in Anthony P. DeCaprio, 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.
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
The XPD protein is an evolutionarily conserved helicase, a subunit of transcription factor IIH (TFIIH) that is essential for transcription and NER (136). Mutations in XPD prevent its protein from interacting with p44, another subunit of TFIIH (137), and decrease helicase activity, resulting in a defect in NER. Furthermore, mutations at different sites result in distinct clinical phenotypes (138). XPD is also thought to be involved in the repair of genetic damage induced by tobacco carcinogens (111).
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].
Targeting the DNA damage response in pediatric malignancies
Published in Expert Review of Anticancer Therapy, 2022
Jenna M Gedminas, Theodore W Laetsch
As opposed to the small base lesions corrected using BER, nucleotide excision repair (NER) removes the bulky DNA lesions caused by UV light, environmental mutagens, and cancer chemotherapy adducts [8]. Once the damage is recognized, transcription factor II H (THFIIH) and XPG are recruited to the site to act as helicases and unwind the DNA. XPG and XPF-ERCC1 then act as endonucleases to cut the DNA on either side of the damage, removing a single strand of 25–30 nucleotides. Proliferating cell nuclear antigen is loaded onto the DNA strand by replication factor C allowing DNA polymerases to copy the undamaged strand. Finally, DNA ligase I and flap endonuclease 1 seal the nicks in the repaired DNA [8]. Poly (ADP-ribose) polymerases (PARPs) are enzymes which play a role in BER and NER, as well as single stranded break repair [9]. PARP binds to sites of DNA strand breaks to facilitate access of the respective repair enzymes to the site [9]. PARP inhibition has shown synthetic lethality with BRCA mutations in the clinical and preclinical setting [9].