DNA polymerase θ protects leukemia cells from metabolically induced DNA damage.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Vekariya Umeshkumar, Toma Monika, Nieborowska-Skorska Margaret, Le Bac Viet, Caron Marie-Christine, Kukuyan Anna-Mariya, Sullivan-Reed Katherine, Podszywalow-Bartnicka Paulina, Chitrala Kumaraswamy N, Atkins Jessica, Drzewiecka Malgorzata, Feng Wanjuan, Chan Joe, Chatla Srinivas, Golovine Konstantin, Jelinek Jaroslav, Sliwinski Tomasz, Ghosh Jayashri, Matlawska-Wasowska Ksenia, Chandramouly Gurushankar, Nejati Reza, Wasik Mariusz, Sykes Stephen M, Piwocka Katarzyna, Hadzijusufovic Emir, Valent Peter, Pomerantz Richard T, Morton George, Childers Wayne, Zhao Huaqing, Paietta Elisabeth M, Levine Ross L, Tallman Martin S, Fernandez Hugo F, Litzow Mark R, Gupta Gaorav P, Masson Jean-Yves, Skorski Tomasz
Аннотация
Leukemia cells accumulate DNA damage, but altered DNA repair mechanisms protect them from apoptosis. 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 [ITD]), JAK2(V617F), BCR-ABL1). 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. Overexpression of POLθ in OTK-positive cells resulted in the efficient repair of DPC-containing DNA double-strand breaks by POLθ-mediated end-joining. 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. Genetic and pharmacological targeting of POLθ polymerase and helicase activities revealed that both activities are promising targets in leukemia cells. Moreover, OTK inhibitors or DPC-inducing drug etoposide enhanced the antileukemia effect of POLθ inhibitor in vitro and in vivo. In conclusion, we demonstrated that POLθ plays an essential role in protecting leukemia cells from metabolically induced toxic DNA lesions triggered by formaldehyde, and it can be targeted to achieve a therapeutic effect.