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Published on: October 6, 2017
Mammalian DNA Polymerase Kappa Activity and Specificity
Hannah R Stern1, Jana Sefcikova1, Victoria E Chaparro1
1Department of Chemistry & Chemical Biology, Northeastern University, Boston, MA 02115, USA.
Abstract:
DNA polymerase (pol) kappa is a Y-family translesion DNA polymerase conserved throughout all domains of life. Pol kappa is special6 ized for the ability to copy DNA containing minor groove DNA adducts, especially N2-dG adducts, as well as to extend primer termini containing DNA damage or mismatched base pairs. Pol kappa generally cannot copy DNA containing major groove modifications or UV-induced photoproducts. Pol kappa can also copy structured or non-B-form DNA, such as microsatellite DNA, common fragile sites, and DNA containing G quadruplexes. Thus, pol kappa has roles both in maintaining and compromising genomic integrity. The expression of pol kappa is altered in several different cancer types, which can lead to genome instability. In addition, many cancer-associated single-nucleotide polymorphisms have been reported in the POLK gene, some of which are associated with poor survival and altered chemotherapy response. Because of this, identifying inhibitors of pol kappa is an active area of research. This review will address these activities of pol kappa, with a focus on lesion bypass and cellular mutagenesis.
Insights
DNA polymerase kappa bypasses DNA damage, including minor groove adducts and structured DNA, but struggles with major groove lesions. Its role in genomic integrity and altered expression in cancer make it a research target.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- DNA polymerase kappa (pol kappa) is a Y-family translesion polymerase found across all life domains.
- Pol kappa specializes in replicating DNA with minor groove adducts and extending damaged primer termini.
Purpose of the Study:
- To review the DNA lesion bypass capabilities of pol kappa.
- To discuss the role of pol kappa in cellular mutagenesis and genomic integrity.
- To highlight the relevance of pol kappa in cancer biology and therapeutic targeting.
Main Methods:
- Literature review of studies on DNA polymerase kappa function.
- Analysis of pol kappa's substrate specificity for various DNA lesions and structures.
- Examination of pol kappa's involvement in DNA repair and mutagenesis pathways.
Main Results:
- Pol kappa efficiently bypasses minor groove DNA adducts (e.g., N2-dG) and structured DNA (microsatellites, G-quadruplexes).
- Pol kappa exhibits limited ability to copy major groove adducts and UV photoproducts.
- Altered pol kappa expression and POLK gene polymorphisms are linked to cancer development and patient outcomes.
Conclusions:
- Pol kappa plays a dual role in maintaining and compromising genomic stability.
- Understanding pol kappa's lesion bypass mechanisms is crucial for cancer research.
- Inhibitors targeting pol kappa are actively being investigated for cancer therapy.
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