![]() HR is the most common pathway for stressed replication fork repair and restart ( 5, 7, 8). As such, replication stress is a common etiology of genomic instability, resulting in either cell death or neoplastic transformation ( 4, 6– 8). DNA damage or nucleotide depletion can induce stalling of the replication machinery ( 3, 4), which can result in replication stress and subsequent fork collapse, with disassociation of the replication apparatus ( 5, 6). Thus, miR223-3p is a negative regulator of the aNHEJ DNA repair and represents a therapeutic pathway for BRCA1- or BAP1-deficient cancers.ĭNA replication is not a smooth and continuous process, but rather prone to interruptions ( 1, 2). Reconstituting the expression of miR223-3p in BRCA1- and BAP1-deficient cancer cells results in reduced repair of stressed replication forks and synthetic lethality. We also discovered that cancer cells deficient in BRCA1 or its obligate partner BRCA1-Associated Protein-1 (BAP1) routinely repress miR223-3p to permit repair of stressed replication forks via aNHEJ. Deletion of the miR223 locus in mice increases PARP1 levels in hematopoietic cells and enhances their risk of unprovoked chromosomal translocations. In most cells, high levels of microRNA (miR) 223–3p repress aNHEJ, decreasing the risk of chromosomal translocations. In this study we have found that miR223-3p decreases expression of PARP1, CtIP, and Pso4, each of which are aNHEJ components. Unlike HR, aNHEJ is nonconservative, and can mediate chromosomal translocations. HR is the major repair pathway for stressed replication forks, but when BRCA1 is deficient, stressed forks are repaired by back-up pathways such as alternative nonhomologous end-joining (aNHEJ). This process underlies the mechanism of the Poly-ADP ribose polymerase-1 (PARP1) inhibitors in clinical use, which target BRCA1 deficient cancers, which is indispensable for homologous recombination (HR) DNA repair. This attribute of cancer cells can be exploited therapeutically, by inhibiting the remaining repair pathway, a process termed synthetic lethality. Cancer cells defective in one DNA repair pathway can become reliant on remaining repair pathways for survival and proliferation. He is an Officer of the Order of Australia, and was, until recently, the Secretary for Science Policy of the Australian Academy of Science.Defects in DNA repair give rise to genomic instability, leading to neoplasia. More recently, Robert has exerted a major influence on science policy and medical and scientific ethics in Australia. He used genetic approaches to study the feasibility of carrier testing for cystic fibrosis in the community, developed noninvasive methods of diagnosing diseases during foetal development in early pregnancy, and assisted many groups in developing countries to apply these techniques. He and his colleagues subsequently pioneered the use of anonymous gene markers to position, then attempt to identify, genes that are mutated to cause cystic fibrosis, myotonic dystrophy, ataxias, coronary artery disease, craniofacial abnormalities, and dementia, for which he was awarded the 1994 King Faisal International Prize for Medicine. His group cloned the human alpha, beta and gamma globin genes from cDNAs, and used them to deduce the genomic structures. Robert Williamson is a molecular geneticist who first worked on haemoglobin synthesis in reticulocytes, and then studied thalassaemias.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |