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Hereditary Breast and Ovarian Cancer
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Germline mutations in BRCA2 [including frameshift deletions, insertions, or nonsense variants such as c.771_775delTCAAA (999del5) yielding p.Asn257LysfsTer17; c.5946delT (6174delT) yielding p.Ser1982ArgfsTer22; c.9976A>T yielding p.Lys3326Ter] result in prematurely a truncated, loss-of-function protein, which introduces errors in DNA phosphorylation and repair and contributes to 25% of familial breast cancer cases. In fact, missense mutations (e.g., D2723H) in the C-terminal region (residues 2500–2850) interfering with the binding of BRCA2 to DSS1 or disrupting RAD51 loading onto damaged chromatin have been detected in >25% of cancer cases. Phosphorylation at Ser3291 by cyclin-dependent kinase (CDK) also interrupts the C-terminal BRCA2–RAD51 interaction [15].
Breast Cancer Stem Cells and Their Niche: Lethal Seeds in Lethal Soil
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Danuta Balicki, Brian Leyland-Jones, Max S. Wicha
In addition to other downstream effectors, the highly branched PI3K pathway activates the mammalian target of rapamycin (mTOR). Molecules such as p21Cipl/Wafl are found downstream to PTEN, and they influence stem cell proliferation, without necessarily implicating self-renewal. FOXO regulatory proteins may have the effects of PTEN on p21Cipl/Wafl by influencing the expression of a range of crucial genes for stem cell function, including cell division, and tolerance of oxidative stress. Thus, the perturbation of PTEN may thus result in nonrenewing cell divisions or death of stem cells (84). PTEN has also been reported to be a guardian of genome integrity and of the maintenance of chromosomal stability through the physical interaction with centromeres and control of DNA repair. PTEN acts on chromatin and regulates the expression of Rad51, which reduces the incidence of spontaneous double strand breaks (86).
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
After the DDR signaling pathways activate the DNA repair machinery in the cell, DSBs are repaired by two distinct pathways such as homologous recombination (HR) and nonhomologous end joining (NHEJ). HR is the most used mechanism in which genetic material is exchanged between sister chromatids to repair the damaged DNA without loss of nucleotides. During HR, the enzymes Rad51 and Dmc1 catalyze pairing and shuffling of homologous DNA sequences in mammalian cells, leading to precise repair of the damaged sites. This process is enhanced by breast tumor suppressor BRCA1/2 [20]. During NHEJ, broken ends are brought together and rejoined by DNA ligation, generally with the loss of one or more nucleotides at the site of joining; hence, it is an error-prone DNA repair mechanism. The protein Ku heterodimer (Ku70 and Ku80) recognizes DSBs and acts as a scaffold to recruit the other NHEJ factors, such as DNA-PKcs, x-ray cross complementing protein 4, DNA ligase IV, XRCC4-like factor, and aprataxin-and-PNK-like factor, to DSBs to complete the ligation process [21]. Recent data showed that pharmacologic ascorbate suppresses the expression of HR repair proteins including BRCA1, BRCA2, and RAD51, thus leading to HR deficiency and sensitizing the BRCA1/2 wild-type epithelial ovarian cancer cells to PARP inhibition [22]. Meanwhile, in the presence of HR deficiency, pharmacologic ascorbate also impeded the NHEJ pathway, leading to DNA repair deficiency [22].
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].
Genetic polymorphisms in DNA repair genes and their association with cervical cancer
Published in British Journal of Biomedical Science, 2019
M Abbas, K Srivastava, M Imran, M Banerjee
DNA-repair systems are necessary for the maintenance of genetic integrity, dysfunction of which will lead to the development of cancer [18]. There are different types of DNA repair system viz. Base-Excision Repair (BER) pathway for single strand breaks (SSBs) and Nucleotide Excision Repair (NER) system for double-strand DNA breaks (DSBs). Principle mechanisms of repair systems are homologous recombination (HR) and non-homologous end joining (NHEJ) [19]. X-ray cross-complementing group 1 (XRCC1) is BER protein that may play an important role to prevent DNA from damaging agents [20]. The important molecules of HRR pathway are RAD51, XRCC2 and XRCC3 [21]. Repair of DSBs is an important component of these genes. Structure and function of XRCC2 and XRCC3 genes are related to the RAD51 gene. RAD51 functional defect results in an increased mutation rate that lead to accumulation of DNA damage and subsequently increased cancer risk [22].
The future impacts of non-targeted effects
Published in International Journal of Radiation Biology, 2018
Currently, immunogenic cell death and the release of damage-associated molecular patterns (DAMP’s), is thought to be of prime importance. These molecular patterns include high mobility group box 1 protein (HMGB1), ATP and calreticulin, the presentation of the latter is processed by dendritic cells which facilitates antigen presentation and cytotoxic T lymphocyte activation (Obeid et al. 2007; Hu et al. 2017). HMGB1 perpetuates an inflammatory environment by stimulating other immune components to produce cytokines (Andersson et al. 2000), while ATP can stimulate IL-1β which can promote tumor immunogenicity (Ghiringhelli et al. 2009). Recent findings have also identified roles for RAD51 in innate immunity. Defects in RAD51 led to increased levels of self DNA in the cytoplasm of irradiated cells, which subsequently activated stimulator of interferon genes (STING), which further adds to the proinflammatory environment. RAD51 is an important protein for DNA repair through homologous recombination and for stalled replication fork processing. The complex damage induced by high LET may generate irreparable damage that leads to cytosolic self DNA. This raises interesting questions and possible links between DNA damage, radiation LET and immune/inflammatory responses.