China
Africa
Explore chapters and articles related to this topic
Vasculitis
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Michelle L. Robinette, Eli Miloslavsky, Zachary S. Wallace
Other monogenic syndromes with associated vasculitis include interferonopathies, inflammasopathies, and relopathies (15). Among these, vasculitis occurs most frequently among some interferonopathies, which mechanistically share increased type I interferon signatures but can diverge in phenotype (36–38). For example, heterozygous gain-of-function mutations in TMEM173, encoding stimulator of interferon genes (STING) downstream of several cytosolic DNA sensors, cause early-onset cutaneous leukocytoclastic vasculitis in STING-associated vasculopathy with onset in infancy (SAVI). In COPA syndrome, autosomal dominant mutations in the coatomer protein complex subunit alpha (COPA) similarly result in prolonged function of activated STING. However, this syndrome presents with a different vascular phenotype than SAVI and is characterized by pediatric-onset pulmonary capillaritis that mimics isolated pulmonary AAV as well as teenage-onset glomerular disease with multiple histopathologic subtypes (39). Additionally, a variety of disease-associated mutations occur in the DNA exonuclease TREX1 and can cause cutaneous vasculopathy reminiscent of SAVI and DADA2 or CNS vasculopathy, with clinically divergent but overlapping phenotypes and inheritance patterns among the four named disease entities (40).
Molecular Radiation Biology
Published in Kedar N. Prasad, Handbook of RADIOBIOLOGY, 2020
DNA synthesis can be induced in all phases of the cell cycle of mammalian cells by such agents as UV rays, X-irradiation, and alkylating agents. This so-called “unscheduled” DNA synthesis is of low magnitude compared with normal DNA synthesis in the S phase, and has been equated to repair activity in damaged cells. Supralethal doses of ionizing radiation (5000–10,000 rads) induce “unscheduled”DNA synthesis in HeLa cells.32 Such an observation has been confirmed in human lymphocytes and other mammalian cells. In addition, a recent report49 shows that significant amounts of 3H-thymidine are incorporated into the DNA of HeLa cells without an extracellular stimulus, and at a time when normal DNA synthesis does not occur. It has been suggested that lesions are introduced into the genome as part of a general error-correcting mechanism or during normal replication and transcription potentiated by exonuclease activity. The spontaneous, unscheduled DNA synthesis may account for the repair of such lesions induced as a part of the cell’s normal metabolic activity. The induction of unscheduled DNA synthesis in mammalian cells by X-irradiation further suggests that such a metabolic event plays a role in the repair of DNA molecules.
DNA Double Strand Breaks and Chromosomal Aberrations
Published in K. H. Chadwick, Understanding Radiation Biology, 2019
At the double strand break (2 stars, pale grey DNA), exonuclease partially degrades each one of the two DNA strands in the 5′P–3′OH direction to make two single stranded tails (a). The single stranded tails are recombinogenic with homologous DNA, either from an undamaged sister chromatid in the G2 phase, or with an undamaged homologous chromosome (black DNA) (b). The homologous association at the single stranded tails leads to an endonuclease ‘nick’ in one strand of the undamaged (black) DNA which allows the strand to pair, by matching complementary bases, with one of the single strand regions at the double strand break (c). This process creates a recombination hetero-duplex, originally proposed by Holliday (1964). Continued unwinding of the undamaged DNA strand extends the hetero-duplex and allows a second hetero-duplex to form between the second single stranded region at the double strand break (pale grey) and the remaining strand of the homologous DNA (black) (d). The single strand gaps (pale grey) can be repaired by complementary base pairing with the two strands of the homologous DNA (black) (e). There are two possible resolutions of the Holliday junction. The DNA unwinds to give the restoration of the original DNA helices and perfect repair (f) (upper drawing) or there is a reciprocal exchange of DNA between the two DNA helices (g) (lower drawing).
The role of immune checkpoint inhibitors for patients with advanced stage microsatellite stable colorectal cancer and high tumor mutation burden: quantity or quality?
Published in Expert Opinion on Biological Therapy, 2023
Charan Thej Reddy Vegivinti, Cyndi Gonzales Gomez, Masood Syed, Morgan Ferrell, Svea Cheng, Aatur Singhi, Anwaar Saeed, Ibrahim Halil Sahin
Pathogenic variants in the exonuclease domain (ED) of polymerases POLE and POLD1 gene mutations are associated with high tumor mutation burden, often above 150 mutations per megabase [9,12]. Somatic POLE/POLD1 exonuclease domain mutations are seen in 1–3% of CRC and are also a potential molecular marker for predicting the efficacy of ICIs [13–15]. POLE and POLD1 belong to the DNA polymerase family and encode catalytic subunits of DNA polymerase ε and polymerase δ, respectively, which play an essential role in proofreading during the synthesis of DNA [13]. Missense mutations are the most common type of mutation seen in MSS CRC with POLE/POLD1 mutations, whereas frameshift deletion mutations represent a critical biological feature of MSI-H CRC. Although POLE/POLD1 mutations are primarily associated with MSS CRC, on rare occasions, POLE/POLD1 mutant CRC can be present in MSI-H disease due to concurrent MMR deficiency [16]. Notably, POLE mutations show excellent prognosis and favorable response to ICIs, probably due to the immune response elicited by neoantigens generated as a consequence of hypermutational status [17]
Molecular radiobiology and the origins of the base excision repair pathway: an historical perspective
Published in International Journal of Radiation Biology, 2023
Homologues of the 5’AP endonucleases exist across phyla. The yeasts S. cerevisiae and S. pombe contain an endo IV-like activity, Apn1 (Popoff et al. 1990). Homologs of exo III are found in eukaryotes including rodents and mammals (Demple et al. 1991; Robson and Hickson 1991; Seki et al. 1991, 1992). The human Xth homolog, APE1, has a much stronger AP hydrolytic activity than E. coli exo III and much weaker activity on the 3′ blocking groups on strand breaks (Kane and Linn 1981; Chen et al. 1991). There is a second homolog of exo III in human cells, APE2 (Hadi and Wilson 2000) that has a very weak AP endonuclease activity but efficient 3′-5′ exonuclease and 3′ diesterase activities (Hadi et al. 2002; Burkovics et al. 2009) and is involved in end resection during single strand break repair (Hossain et al. 2018).
The successful strategy of comprehensive pre-implantation genetic testing for beta-thalassaemia–haemoglobin E disease and chromosome balance using karyomapping
Published in Journal of Obstetrics and Gynaecology, 2022
Sirivipa Piyamongkol, Suchada Mongkolchaipak, Pimlak Charoenkwan, Rungthiwa Sirapat, Wanwisa Suriya, Tawiwan Pantasri, Theera Tongsong, Wirawit Piyamongkol
Mini-sequencing was employed for mutation analysis of beta-thalassaemia (c.17A>T) and Hb E disease. Amplified PCR products were treated with Exonuclease I/Alkaline Phosphatase using ExoProStarTM 1-Step (Bang Trading 1992 Co., Ltd., Bangkok, Thailand) to remove unincorporated primers and dNTPs from PCR reactions before DNA sequencing. 2.14 μL of the PCR products were added into 0.2-mL microcentrifuge tubes containing 0.86 µL of ExoProStarTM 1-Step and incubated at 37 °C for 30 min, followed by 80 °C for 15 min. A mini-sequencing reaction mixture was set up on ice and comprised 5.0 μL of SNaPshot® Multiplex Kit (GenePlus Co., Ltd., Bangkok, Thailand), 0.5 μL of primer (0.2 µM stock) (anti-sense beta-thalassaemia (c.17A>T) 5′-CCG TTA CTG CCC TGT GGG GC-3′ or Hb E disease (c.26G>A) 5′-ACG TGG ATG AAG TTG GTG GT-3′), 3.0 μL of the purified template and distilled deionised water in a total volume of 10 μL. Thermal cycles were performed with the following conditions: 96 °C for 10 s, 50 °C for 5 s and 60 °C for 30 s for 25 cycles.