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Roles of trans-lesion synthesis (TLS) DNA polymerases in tumorigenesis and cancer therapy.

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Date
2023-03
Authors
Anand, Jay
Chiou, Lilly
Sciandra, Carly
Zhang, Xingyuan
Hong, Jiyong
Wu, Di
Zhou, Pei
Vaziri, Cyrus
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Abstract
DNA damage tolerance and mutagenesis are hallmarks and enabling characteristics of neoplastic cells that drive tumorigenesis and allow cancer cells to resist therapy. The 'Y-family' trans-lesion synthesis (TLS) DNA polymerases enable cells to replicate damaged genomes, thereby conferring DNA damage tolerance. Moreover, Y-family DNA polymerases are inherently error-prone and cause mutations. Therefore, TLS DNA polymerases are potential mediators of important tumorigenic phenotypes. The skin cancer-propensity syndrome xeroderma pigmentosum-variant (XPV) results from defects in the Y-family DNA Polymerase Pol eta (Polη) and compensatory deployment of alternative inappropriate DNA polymerases. However, the extent to which dysregulated TLS contributes to the underlying etiology of other human cancers is unclear. Here we consider the broad impact of TLS polymerases on tumorigenesis and cancer therapy. We survey the ways in which TLS DNA polymerases are pathologically altered in cancer. We summarize evidence that TLS polymerases shape cancer genomes, and review studies implicating dysregulated TLS as a driver of carcinogenesis. Because many cancer treatment regimens comprise DNA-damaging agents, pharmacological inhibition of TLS is an attractive strategy for sensitizing tumors to genotoxic therapies. Therefore, we discuss the pharmacological tractability of the TLS pathway and summarize recent progress on development of TLS inhibitors for therapeutic purposes.
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Journal article
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https://hdl.handle.net/10161/26685
Published Version (Please cite this version)
10.1093/narcan/zcad005
Publication Info
Anand, Jay; Chiou, Lilly; Sciandra, Carly; Zhang, Xingyuan; Hong, Jiyong; Wu, Di; ... Vaziri, Cyrus (2023). Roles of trans-lesion synthesis (TLS) DNA polymerases in tumorigenesis and cancer therapy. NAR cancer, 5(1). pp. zcad005. 10.1093/narcan/zcad005. Retrieved from https://hdl.handle.net/10161/26685.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Hong

Jiyong Hong

Professor of Chemistry
Research in the Hong group focuses on using chemical tools, in particular small molecules, to understand the signaling pathways in biology. We synthesize biologically interesting natural products and screen small molecule libraries to identify modulators of biological processes. Then, we explore their modes of action in order to investigate intracellular signaling pathways and identify novel targets for drug design. In addition, we design and develop unique and efficient synthetic strategies tha
Zhou

Pei Zhou

Professor of Biochemistry
Protein-protein interactions play a pivotal role in the regulation of various cellular processes. The formation of higher order protein complexes is frequently accompanied by extensive structural remodeling of the individual components, varying from domain re-orientation to induced folding of unstructured elements. Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful tool for macromolecular structure determination in solution. It has the unique advantage of being capable of elucidati
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