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Artículo

Chk1 loss creates replication barriers that compromise cell survival independently of excess origin firing

González, Marina AlejandraIcon ; Calzetta, Nicolás LuisIcon ; Loureiro, Sofía M.; Habif, MartinIcon ; Bétous, Rémy; Pillaire, Marie Jeanne; Maffia, Antonio; Sabbioneda, Simone; Hoffmann, Jéan Sebastién; Gottifredi, VanesaIcon
Fecha de publicación: 06/2019
Editorial: Nature Publishing Group
Revista: Embo Journal
ISSN: 0261-4189
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Biología Celular, Microbiología

Resumen

The effectiveness of checkpoint kinase 1 (Chk1) inhibitors at killing cancer cells is considered to be fully dependent on their effect on DNA replication initiation. Chk1 inhibition boosts origin firing, presumably limiting the availability of nucleotides and in turn provoking the slowdown and subsequent collapse of forks, thus decreasing cell viability. Here we show that slow fork progression in Chk1-inhibited cells is not an indirect effect of excess new origin firing. Instead, fork slowdown results from the accumulation of replication barriers, whose bypass is impeded by CDK-dependent phosphorylation of the specialized DNA polymerase eta (Polη). Also in contrast to the linear model, the accumulation of DNA damage in Chk1-deficient cells depends on origin density but is largely independent of fork speed. Notwithstanding this, origin dysregulation contributes only mildly to the poor proliferation rates of Chk1-depleted cells. Moreover, elimination of replication barriers by downregulation of helicase components, but not their bypass by Polη, improves cell survival. Our results thus shed light on the molecular basis of the sensitivity of tumors to Chk1 inhibition.
Palabras clave: CHECKPOINT KINASE 1 , ORIGIN FIRING , REPLICATION BARRIER , REPLICATIVE HELICASE , TRANSLESION DNA POLYMERASE ETA
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info:eu-repo/semantics/restrictedAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/97954
DOI: http://dx.doi.org/10.15252/embj.2018101284
URL: https://www.embopress.org/doi/abs/10.15252/embj.2018101284
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Articulos(IIBBA)
Articulos de INST.DE INVEST.BIOQUIMICAS DE BS.AS(I)
Citación
González, Marina Alejandra; Calzetta, Nicolás Luis; Loureiro, Sofía M.; Habif, Martin; Bétous, Rémy; et al.; Chk1 loss creates replication barriers that compromise cell survival independently of excess origin firing; Nature Publishing Group; Embo Journal; 38; 16; 6-2019; 1-35; e101284https
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