China
Africa
Explore chapters and articles related to this topic
Cutaneous Malignant Melanoma
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The NBS1 (Nijmegen breakage syndrome 1) gene on chromosome 8q21.3 measures 69.8 kb in length and encodes a 754 aa, 84.9 kDa protein (NBN or nibrin, also referred to as p95). Nibrin interacts with MRE11 and RAD50 to form the MRN complex, which possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity and participates in double-strand break (DSB) repair. In addition, nibrin plays a role in the maintenance of telomere length and thus chromosome integrity, and also in the control of intra-S-phase checkpoint. Besides its implication in Nijmegen breakage syndrome, an autosomal recessive disorder characterized by spontaneous chromosomal instability, immunodeficiency, and predisposition to cancer, the NBS1 gene may be also involved in malignant melanoma.
Pharmacologic Ascorbate Influences Multiple Cellular Pathways Preferentially in Cancer Cells
Published in Qi Chen, Margreet C.M. Vissers, Cancer and Vitamin C, 2020
Qi Chen, Kishore Polireddy, Ping Chen, Ramesh Balusu, Tao Wang, Ruochen Dong
A complex network of signaling pathways is altered when cells are exposed to DNA damaging agents [15]. Like other signaling pathways, a DNA damage response (DDR) signaling pathway consists of sensors, transducers, and effectors [16]. DNA damage sensors are the proteins that directly recognize aberrant DNA structures. Mre11-Rad50-Nbs1 (MRN) complex is the key sensor of DNA damage in mammalian cells; it activates ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) kinases, two key transducers of the complex DDR network signaling. Pharmacologic ascorbate activates ATM in a concentration- and time-dependent manner by inducing ATM phosphorylation, and this phosphorylation can be rescued by catalase [4,13]. Following the initial activation, ATM triggers phosphorylation of histone 2Ax (H2Ax), which is a critical event for accumulation of numerous DNA repair proteins and chromatin-remodeling complexes around the DSBs [4,14]. Chk2, another downstream effector of ATM and ART, was also activated by ascorbate treatment [13]. It is also proposed that other downstream targets of ATM and ATR kinases (e.g., BRCA1/2, and p53) [17] are influenced by ascorbate treatment, which are primarily involved in a broad spectrum of cellular processes important for genomic stability and influence cell survival, cell cycle, apoptosis, and senescence [18,19].
Irradiation-induced damage and the DNA damage response
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Conchita Vens, Marianne Koritzinsky, Bradly G. Wouters
The third kinase that quickly responds to DNA damage and is capable of phosphorylating H2AX is ATR. In contrast to ATM and DNA-PKcs, ATR does not appear to play any substantial role in signalling initiated by radiation-induced DSBs. Instead, it phosphorylates H2AX in response to other types of DNA damage and abnormalities such as single-stranded DNA and stalled or broken replication forks. ATR is thus very important for the types of damage that occur during normal DNA replication. Single-stranded DNA regions coated with RPA recruit the mediator protein ATRIP (ATR interacting protein) and ATR. Although ATR is less important in the initial processing of radiation-induced DSBs, it does play a role in this pathway after ATM is activated. Activation of the ATM-MRN complex leads to processing of the DNA at sites of DSB. This processing can create stretches of single-stranded DNA through extensive DSB end resection, which will then activate ATR. Thus, ATR can be activated ‘downstream’ of ATM activation. ATR is also activated as a consequence of replication problems following irradiation. DNA strand cross links and oxidized bases caused by radiation interfere with replication and activate ATR (20). ATR shares some of the phosphorylation targets of ATM but also phosphorylates a distinct set of proteins that participate in the DDR. Consequently, components of the DDR effector pathways (DNA repair, checkpoints and cell death) are also dependent on ATR after radiation treatment. For example, the ATR kinase phosphorylates crucial checkpoint proteins such as CHK1, thereby providing a strong link to cell-cycle regulation.
The crosstalk between DNA damage response components and DNA-sensing innate immune signaling pathways
Published in International Reviews of Immunology, 2022
Feng Lin, Yan-Dong Tang, Chunfu Zheng
The multifunctional DDR protein complex MRN involves regulating stalled replication forks, dysfunctional telomeres, and viral DNA replication [34]. MRE11 coordinating with RAD50 recognizes intracellular dsDNA to activate the MRE11-STING signaling pathway, while another MRN complex component, NBS1, is dispensable. The MRE11 exclusively recognizes exogenous dsDNA, but not damaged host DNA, to induce IFN-β production. MRE11 or RAD50 does not recognize the pathogenic DNA [35], suggesting that MRE11 mediates the limited production of IFN-I as a DNA sensor, which may benefit in preventing DNA-associated autoimmunity. MUS81 (MMS and UV-sensitive protein 81) protein belonging to the XPF/MUS81 endonuclease family plays an important role in repairing DNA lesions caused by UV-light, DNA crosslinking agents, and replication fork collapse [36]. The cleavage of genomic DNA by MUS81 and PARP-dependent DNA repair pathways results in the accumulation of cytosolic DNA, which leads to the STING-dependent production of IFN-I and chemokines [37]. But the direct role of MUS81 involved in the DNA sensing innate immune signaling pathway is not well understood, and further experimental evidence is required to completely understand how MUS81 contributes to the innate immune signaling pathway.
Investigational PARP inhibitors for the treatment of biliary tract cancer: spotlight on preclinical and clinical studies
Published in Expert Opinion on Investigational Drugs, 2021
Rutika Mehta, Anthony C Wood, James Yu, Richard Kim
BRCA1/2 mutations are reported in up to 5.0% of all BTCs with BRCA2 mutations more frequently reported in GBCs [5,13,28]. Both BRCA1 and BRCA2 are involved in the HR repair (hereafter referred to as HRR) process, which plays a major role in DSB repair. A DSB is detected by an MRN complex comprised of the meiotic recombination 11 homologue A (MRE11A)-Nijmegen breakage syndrome 1 (NSB1)-RAD50. BRCA1 now aids in the resection of 5ʹ DNA on either side of DSB, thus exposing single-strand DNA (ssDNA). With the help of BRCA2, DNA recombinase RAD51 is localized to the ssDNA. This RAD51 bound to DNA forms a nucleoprotein that initiates the homologous repair process. With the help of ligases and endonucleases, a successful HRR is completed. When HRR fails, such as when homologous DNA is unavailable, DNA is repaired by end joining, which usually results in DNA deletions. If these deletions occur is crucial tumor suppressor genes, then these lead to tumorigenesis [21]. In vitro studies have shown that mouse cell lines lacking Brca1 or Brca2 have enhanced use of NHEJ, and this leads to higher frequency of DNA deletions [29].
Ataxia-telangiectasia: epidemiology, pathogenesis, clinical phenotype, diagnosis, prognosis and management
Published in Expert Review of Clinical Immunology, 2020
Parisa Amirifar, Mohammad Reza Ranjouri, Martin Lavin, Hassan Abolhassani, Reza Yazdani, Asghar Aghamohammadi
ATM is the most frequently reported gene related to A-T clinical manifestations. However, a few cases have been attributed to MRE11 deficiency in early reports, and a minority of patients do not yet have a monogenic cause. Mutations in MRE11 were subsequently shown to be associated with a related but distinct disorder [23]. The ATM gene contains 66 exons (spanning 150 kb of genomic DNA) with 12 protein-encoding transcripts making a range of products from 93 to 3056 amino acids. The full-length ATM protein plays a major role in the molecular response to DNA-DSBs. ATM is rapidly activated by DNA damage and recruited to sites of damage by the MRN complex (MRE11-RAD50-NBS1) via its interaction with the C-terminal domain of NBS1. ATM activation is linked with different posttranslational modifications of the protein, including autophosphorylation at several different sites (Figure 1) [24,25].