![]() ![]() Genetic and pharmacological targeting of POLθ polymerase and helicase activities revealed that both activities are promising targets in leukemia cells. The transforming activities of OTKs and other leukemia-inducing oncogenes, especially of those causing the inhibition of BRCA1/2-mediated homologous recombination with and without concomitant inhibition of DNA-PK–dependent nonhomologous end-joining, was abrogated in Polq−/− murine bone marrow cells. Overexpression of POLθ in OTK-positive cells resulted in the efficient repair of DPC-containing DNA double-strand breaks by POLθ-mediated end-joining. To counteract this effect, OTKs enhanced the expression of DNA polymerase theta (POLθ) via ERK1/2 serine/threonine kinase-dependent inhibition of c-CBL E3 ligase-mediated ubiquitination of POLθ and its proteasomal degradation. We showed here that formaldehyde generated by serine/1-carbon cycle metabolism contributed to the accumulation of toxic DNA-protein crosslinks (DPCs) in leukemia cells, especially in driver clones harboring oncogenic tyrosine kinases (OTKs: FLT3(internal tandem duplication ), JAK2(V617F), BCR-ABL1). Leukemia cells accumulate DNA damage, but altered DNA repair mechanisms protect them from apoptosis. Gupta, Jean-Yves Masson, Tomasz Skorski DNA polymerase θ protects leukemia cells from metabolically induced DNA damage. ![]() Pomerantz, George Morton, Wayne Childers, Huaqing Zhao, Elisabeth M. Sykes, Katarzyna Piwocka, Emir Hadzijusufovic, Peter Valent, Richard T. ![]() Chitrala, Jessica Atkins, Malgorzata Drzewiecka, Wanjuan Feng, Joe Chan, Srinivas Chatla, Konstantin Golovine, Jaroslav Jelinek, Tomasz Sliwinski, Jayashri Ghosh, Ksenia Matlawska-Wasowska, Gurushankar Chandramouly, Reza Nejati, Mariusz Wasik, Stephen M. Umeshkumar Vekariya, Monika Toma, Margaret Nieborowska-Skorska, Bac Viet Le, Marie-Christine Caron, Anna-Mariya Kukuyan, Katherine Sullivan-Reed, Paulina Podszywalow-Bartnicka, Kumaraswamy N. ![]()
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