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Characterization of Lysine Methyltransferase 2C and 2D in DNA Damage Response and Repair in Non-Small Cell Lung Cancer

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abstract
Methylation of histone 3 at lysine 4 via lysine methyltransferases KMT2A-D results in a relaxed chromatin state, leading to transcriptional activation. In non-small cell lung cancer (NSCLC) we report that KMT2 gene mutations, especially those of KMT2C and KMT2D occur often and are correlated with poor survival. We show that KMT2C and KMT2D play an important role in DNA damage response (DDR) and repair. We identify KMT2C/D as being directly recruited to double strand break (DSB) sites, and through histone methylation induce chromatin relaxation conducive for the recruitment of DDR factors and repair proteins. We show that KMT2C and KMT2D are required for homologous recombination (HR), as disruption of either gene via shRNAs results in reduced HR-mediated repair. Through this disruption in repair, we show that mutations in KMT2C and KMT2D sensitize NSCLC cells to PARP inhibitors (PARPi). Our findings have established a previously unknown critical role for KMT2C and KMT2D in DDR and repair. There is a paucity of biomarkers available for predicting response to PARPi therapy in lung cancer. Our data indicate that KMT2C and KMT2D mutations may be clinically relevant biomarkers in NSCLC.
subject
contributor
Ashby, Justin (author)
Sun, Peiqing (committee chair)
Sun, Peiqing (committee member)
Metheny-Barlow, Linda J (committee member)
Vidi, Pierre-Alexandre (committee member)
date
2020-05-29T08:35:46Z (accessioned)
2020-05-29T08:35:46Z (available)
2020 (issued)
degree
Biomedical Science – MS (discipline)
identifier
http://hdl.handle.net/10339/96806 (uri)
language
en (iso)
publisher
Wake Forest University
title
Characterization of Lysine Methyltransferase 2C and 2D in DNA Damage Response and Repair in Non-Small Cell Lung Cancer
type
Thesis

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