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Radiobiology of Tumours
Published in W. P. M. Mayles, A. E. Nahum, J.-C. Rosenwald, Handbook of Radiotherapy Physics, 2021
Gordon Steel, Catharine West, Alan Nahum
The speed of cellular recovery has been measured in many cell and tissue types. There is evidence, mainly from DNA repair studies, that recovery is a multi-exponential process with a first component half-time of a few minutes, a main component whose half-time may be approximately 1 hour, and perhaps also an even slower component. The clinical implication of this is that if treatment is given with multiple fractions per day, it is important to allow full recovery between fractions. This may require an inter-fraction gap of at least 6 hours (see Section 8.6.4). Research elucidating the molecular mechanisms involved in radiation-induced DNA damage response and repair has led to interest in targeting the pathways to identify new agents to combine with radiotherapy (Morgan and Lawrence 2015).
BRCA Mutation and PARP Inhibitors
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Arjun Mittra, James H. Doroshow, Alice P. Chen
Cells undergo DNA damage during replication and from environmental exposures. Increasing evidence implicates defects in the DNA repair pathway in carcinogenesis, cancer progression, and response to therapy [49]. Damaged cells repair DNA through a system of molecular interactions called the DNA damage response (DDR) pathway. This process allows the integrity of the genome to be maintained; damage to DNA is identified, the cell cycle is halted, and DNA repair is effected [75]. Multiple cellular response mechanisms are involved in the repair of DNA damage, including base excision repair (BER), mismatch repair (MMR), nucleotide excision repair (NER), single strand annealing (SSA), “error free” homologous recombination (HR), and “error prone” non-homologous end joining (NHEJ).
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].
Role of DNA damage and repair in radiation cancer therapy: a current update and a look to the future
Published in International Journal of Radiation Biology, 2020
Jingya Liu, Kun Bi, Run Yang, Hongxia Li, Zacharenia Nikitaki, Li Chang
Evolution equipped organisms, and mostly mammals, with an arsenal of enzymes and processes capable to defend their DNA damage integrity, by enormous probability of success. This is the DNA damage response, a network of interacting pathways which detects DNA lesions, sends the appropriate signals and ultimately repairs the damage. Upon damage induction, DDR begins with sensor proteins that recognize the damage, attract and activate signal transduction protein kinases (transducer kinases). Transducer kinases ‘alert’ the upstream effector kinases, which modificate the downstream effector kinases (Pateras et al. 2015). The later recruit the appropriate molecules to repair the damage. Depending on damage complexity level one or more of the following pathways are taking place.
Curcumin induces DNA damage by mediating homologous recombination mechanism in triple negative breast cancer
Published in Nutrition and Cancer, 2020
Gamze Guney Eskiler, Elvan Sahin, Asuman Deveci Ozkan, Ozlem Tugce Cilingir Kaya, Suleyman Kaleli
DNA damage response is regulated by different pathways including base excision repair (BER), mismatch repair (MMR), non-homologous end joining (NHEJ) and homologous recombination (HR)-associated genes such as BRCA1/2, RAD50/51, PALB2, CHEK2, BARD1, BRIP1 etc. The BRCA1 gene plays a crucial role in HR mechanism in response to DNA double-strand breaks (dsDNA). BRCA1 interacts with RAD51 to repair dsDNA breaks and maintain genomic stability and thus, BRCA1 and RAD51 are the main mediator of HR mechanism (9–12). Furthermore, phosphorylation of H2AX (γH2AX) is an important step in recruitment of DNA repair proteins and thus, BRCA1, RAD50, and NBS1 localize with γ-H2AX at sites of DNA damage (13,14). Additionally, DNA breaks are also recognized by poly (ADP-ribose) polymerase 1 (PARP1) and thus PARP1 mediates both DNA repair and cell death (15,16). Therefore, the association H2AX, PARP1, BRCA1, and RAD51 with DNA repair and DNA-damage-induced cell death should be further elucidated.
An update on: molecular genetics of high-risk chronic lymphocytic leukemia
Published in Expert Review of Hematology, 2020
Riccardo Moia, Andrea Patriarca, Clara Deambrogi, Silvia Rasi, Chiara Favini, Ahad Ahmed Kodipad, Mattia Schipani, Gianluca Gaidano
Chemotherapy agents exert their antineoplastic activity by interfering with the normal structure of cellular genomic DNA. In normal cells, if the DNA damage induced by chemotherapy cannot be restored by the physiological DNA repairing enzymes, a cascade of intracellular signaling (namely, related to TP53 and ATM functions) causes the apoptosis of the cell. On these grounds, the correct function of the proteins involved in the DNA damage response machinery is essential for inducing cell death in cells treated with chemotherapy. Among these proteins, TP53 plays a pivotal role in the DNA repair pathway. Loss of TP53 function, by mutation and/or deletion, can prevent cell apoptosis, thus leading to the survival and subsequent proliferation of cells with an increased degree of complexity in the number and type of chromosomal and genetic abnormalities [14,15].