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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].
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].
Cyclin-dependent kinase inhibition and its intersection with immunotherapy in breast cancer: more than CDK4/6 inhibition
Published in Expert Opinion on Investigational Drugs, 2022
Xianan Guo, Huihui Chen, Yunxiang Zhou, Lu Shen, Shijie Wu, Yiding Chen
CDK7 participates in the regulation of transcription as part of the human transcription factor II (TFIIH) complex, which also includes cyclin H and Menage a trois 1 (MAT1) [23]. The activation of CDK7 is attributed to binding cyclin H and MAT1, which phosphorylation of its activation segment [24]. Functional CDK7 triggers the phosphorylation of RNAP II at Ser5 and Ser7 [25,26]. Modified Ser5 promotes RNAP II to escape from the preinitiation complex and in turn drive transcription initiation (Figure 1) [27]; however, it is not well understood how phosphorylated Ser7 facilitates this mechanism. Besides, CDK7 is also involved in the pausing, release, and elongation processes of transcription. The recruitment of DRB sensitivity inducing factor (DSIF) and the negative elongation factor (NELF), two complexes required for pausing RNAP II, is mediated by CDK7 (Figure 1) [23,28]. Likewise, CDK7 activates CDK9, a regulator with a role in RNAP II release and RNA chain elongation, to indirectly assist in these phases (Figure 1) [23]. Notably, although CDK7 aids in both pausing and release, inhibition of CDK7 tends to keep RNAP II paused at promoter-proximal regions [25,29].
Therapeutic options in thymomas and thymic carcinomas
Published in Expert Review of Anticancer Therapy, 2022
Although TETs have been classified based on histological appearance using the WHO classification system, many studies on the molecular analysis of TETs have been conducted over the past 20 years [6]. According to the Cancer Genome Atlas project, types A and AB belong to the same spectrum of tumors, and there is little overlap with the spectrum of type B thymomas. Furthermore, the spectrum of thymic carcinomas is completely different from those of type A, AB, and B based on genomic hallmarks by RNA-seq [6]. The mutation in general transcription factor II was found in approximately 80% of patients with type A or AB thymomas and was correlated with better survival. In addition, a large miRNA cluster on chromosome 19q 13.42 is commonly overexpressed in types A and AB [6]. Loss-of-function mutation of tumor protein 53 is detected in 18.5%–26% of TETs (especially in thymic carcinomas) and is associated with poor overall survival (OS) [7]. RAS proteins are also frequently mutated in 7%–18.5% of TETs [7]. Furthermore, thymic carcinomas are characterized by the loss of chromosome 16q. In NUT carcinoma, single chromoplexy was discovered to cause the formation of NUT-fusion oncoproteins [8]. Further molecular analysis of TETs is expected to advance and contribute to the establishment of new classifications.