Roles of trans-lesion synthesis (TLS) DNA polymerases in tumorigenesis and cancer therapy.
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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https://hdl.handle.net/10161/26685Published Version (Please cite this version)
10.1093/narcan/zcad005Publication 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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Show full item recordScholars@Duke
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
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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