Exploring and exploiting the systemic effects of deregulated replication licensing. (June 2016)

• Record Type: Journal Article
• Authors: Petrakis, Theodoros G.; Komseli, Eirini-Stavroula; Papaioannou, Marilena; Vougas, Kostas; Polyzos, Alexandros; Myrianthopoulos, Vassilios; Mikros, Emmanuel; Trougakos, Ioannis P.; Thanos, Dimitris; Branzei, Dana; Townsend, Paul; Gorgoulis, Vassilis G.
• Is Part Of: Seminars in cancer biology. Volume 37/38(2016)
• Page Start: 3
• Page End: 15
• Publication Date: 2016-06
• Subjects: Cdc6 -- Cdt1 -- Replication licensing factors -- Replication stress -- Cancer; RS replication stress -- DDR DNA damage response -- RLM replication licensing machinery -- pre-RC pre-replication complex -- CDK cyclin-dependent kinase -- ORC origin recognition complex -- Cdc6 cell division cycle 6 -- Cdt1 cell division cycle 10-dependent transcript 1 -- MCM minichromosome maintenance -- DDK Dbf4-dependent kinase -- pre-IC pre-initiation complex -- RLFs replication licensing factors -- pRb phospho-retinoblastoma -- UTR untranslated region -- miRs micro-RNAs -- MGS Meier–Gorlin syndrome -- DSBs double-strand breaks -- RPA replication protein A -- CFSs common fragile sites -- HBECs human bronchial epithelial cells -- ATM ataxia telangiectasia mutated -- ARF alternative reading frame -- NK natural killer -- PCNA proliferating cell nuclear antigen -- EMT epithelial to mesenchymal transition -- ESC/iPSC embryonic stem cell/induced pluripotent stem cell -- SDF-1 stromal derived factor-1 -- ICAM1 intercellular adhesion molecule-1 -- ChIP chromatin immune-precipitation -- LC–MS/MS liquid chromatography–tandem mass spectrometry -- AAA+ ATPases associated with a variety of cellular activities -- TK tyrosine kinases -- TKIs tyrosine kinase inhibitors -- TSS transcription start site; Cancer -- Periodicals; Neoplasms -- Periodicals; Review Literature; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.semcancer.2015.12.002
• Languages: English
• ISSNs: 1044-579X

Abstract

Abstract: Maintenance and accurate propagation of the genetic material are key features for physiological development and wellbeing. The replication licensing machinery is crucial for replication precision as it ensures that replication takes place once per cell cycle. Thus, the expression status of the components comprising the replication licensing apparatus is tightly regulated to avoid re-replication; a form of replication stress that leads to genomic instability, a hallmark of cancer. In the present review we discuss the mechanistic basis of replication licensing deregulation, which leads to systemic effects, exemplified by its role in carcinogenesis and a variety of genetic syndromes. In addition, new insights demonstrate that above a particular threshold, the replication licensing factor Cdc6 acts as global transcriptional regulator, outlining new lines of exploration. The role of the putative replication licensing factor ChlR1/ DDX11, mutated in the Warsaw Breakage Syndrome, in cancer is also considered. Finally, future perspectives focused on the potential therapeutic advantage by targeting replication licensing factors, and particularly Cdc6, are discussed.