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Xeroderma Pigmentosum
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Mammalian cells are constantly exposed to UV/ionizing radiation, reactive oxygen species (ROS), replication errors, and chemotherapy that cause DNA damage, cell death, premature aging, and tumorigenesis. Several DNA repair mechanisms are employed by mammalian cells to prevent the consequences of DNA injuries and to preserve genetic integrity. These include (i) base excision repair (BER) for oxidative lesions, (ii) NER for helix-distorting lesions caused by UV radiation, (iii) translesion synthesis for various lesions, (iv) mismatch repair (MMR) for replication errors, (v) single-strand break repair (SSBR) for single-strand breaks caused by ionizing radiation and ROS, (vi) homologous recombination (HR) for double-strand breaks caused by ionizing radiation and ROS, (vii) non-homologous end joining (NHEJ) for double-strand breaks caused by ionizing radiation and ROS, and (viii) DNA interstrand crosslink repair pathway for interstrand crosslinks due to chemotherapy [6].
The Molecular and Genetic Effects of Ultraviolet Radiation Exposure on Skin Cells
Published in Henry W. Lim, Herbert Hönigsmann, John L. M. Hawk, Photodermatology, 2007
Marjan Garmyn, Daniel B. Yarosh
DNA that has modified bases (such as 8oG) is repaired by base excision repair, which replaces only the damaged base and a few neighboring bases. In either case, the opposite undamaged strand of DNA is used as a template to resynthesize the DNA sequence. This type of DNA repair occurs at anytime nearly anywhere in the genome [global genomic repair (GGR)]. However, localized regions of transcribed DNA are repaired much faster by a group of proteins performing transcription-coupled repair (TCR). They are attracted to the site by a transcription fork that has stalled, and TCR accelerates repair of the transcribed strand. If a lesion is not repaired by the time the DNA must be replicated, damage-specific polymerases eta or zeta can insert bases to allow continued replication in a process called translesion synthesis (4). If all these measures fail and too much DNA damage remains, the cell activates a suicide pathway call apoptosis.
Evaluating the influences of confounding variables on benchmark dose using a case study in the field of ionizing radiation
Published in International Journal of Radiation Biology, 2022
Nadine Adam, Ngoc Q. Vuong, Hailey Adams, Byron Kuo, Afshin Beheshti, Carole Yauk, Ruth Wilkins, Vinita Chauhan
The 412 genes modeled by BMD across all groups were associated with a total of 25 pathways. An accumulation plot of the total pathways and their associated BMD median values show that the M-NS curve had a unique profile in comparison to the other three groups, where more pathways fit models at lower BMD values (Figure 5B, green curve). There were 14 (F-NS) and 19 (M-NS) pathway BMDs derived for the nonsmoker groups, and 15 (F-S) and 11 (M-S) pathways for the smoker groups (Figure 6A and 7, and Table S2). A total of one (F-NS), seven (M-NS), one (F-S), and two (M-S) unique pathway(s) were identified for each of the groups. However, the majority of these unique pathways displayed broad confidence intervals (Figure S1). Three pathways with narrow confidence intervals included: “Damage Bypass,” “Translesion Synthesis of POLH” and “Translesion Synthesis by Y family DNA polymerases bypasses lesions on DNA template,” which were modeled only in the male nonsmoker group. Nine of the 25 pathways (36%) were common to all four groups (Figure 6A and 7 and Table S2), and an additional 20% were common to at least two groups. Hierarchical cluster analysis of the BMDs of the nine common pathways shows some small differences between males and females as well as smokers and nonsmokers (Figure 6B); however, pathway BMDL to BMDU plots for each pathway were largely overlapping (Figure S1).
Targeting translesion synthesis (TLS) to expose replication gaps, a unique cancer vulnerability
Published in Expert Opinion on Therapeutic Targets, 2021
Sumeet Nayak, Jennifer A. Calvo, Sharon B. Cantor
Conventionally, RS deriving from DNA lesions are thought to be countered by lesion tolerance mechanisms such as translesion synthesis (TLS). Lower-fidelity TLS polymerases facilitate polymerization across from a DNA lesion in cases where the high-fidelity DNA replicative polymerases stall and cannot replicate past the lesion [31]. One critical point of regulation that engages TLS is the mono-ubiquitination of lysine 164 (K164) of proliferating cell nuclear antigen (PCNA) that is mediated by the RAD18/RAD6 ubiquitin ligases, which initiates the switch from replicative to TLS polymerases. This ubiquitination serves as a platform to recruit TLS polymerases (POL η, POL ι, POL κ, REV1, POL ζ [also known as REV3/REV7], POL θ, and POL ν) that mediate lesion bypass either in the course of DNA replication or in a process of post-replication gap filling [32–38]. By interacting with one or more TLS polymerases, PCNA functions as a ‘tool belt’ to coordinate TLS polymerases in a concerted response that initiates with a TLS polymerase such as POL η or POL κ that inserts a nucleotide at the site of the lesion [39–43]. Extension past the lesion is mediated by a distinct TLS polymerase such as POL ζ followed by a final switch to the replicative polymerases [44,45]. Alternatively, TLS can be engaged independently of PCNA ubiquitination (PCNA Ub) via a REV1 scaffold domain ‘bridge’ that interacts with several TLS polymerases [46,47]. PRIMPOL, a DNA primase and TLS polymerase, can also operate independently of PCNA to restart stalled forks or re-prime replication ahead of a lesion [48–50]. These well-orchestrated TLS polymerase switching events and their regulating mechanisms are reviewed at length in the following articles [51–54].
Macular and Retinal Nerve Fibre Layer Thinning in Xeroderma Pigmentosum: A Cross-sectional Study
Published in Neuro-Ophthalmology, 2018
Anna M. Gruener, Ana M. S. Morley
Mutations in eight different genes give rise to seven complementation groups (XP-A through to XP-G) and a so-called variant type (XP-V).8 All patients with XP, with the exception of XP-V, have defects in genes coding for proteins involved in nucleotide excision repair (NER).9,10 The XP-C and XP-E proteins are solely implicated in global genome NER, whereas the other XP proteins (XP-A, XP-B, XP-D, XP-F, and XP-G) are involved in the global and also the transcription-coupled repair pathway. Patients with the variant type (XP-V) have defects in DNA polymerase ɳ and therefore have normal NER but are defective in translesion synthesis.