{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Moeglin E"],"funding":["Ligue Contre le Cancer","European Research Council","Eucor - The Campus European"],"pagination":["E355"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6468890"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["11(3)"],"pubmed_abstract":["Phosphorylated histone H2AX (γ-H2AX), a central player in the DNA damage response (DDR), serves as a biomarker of DNA double-strand break repair. Although DNA damage is generally visualized by the formation of γ-H2AX foci in injured nuclei, it is unclear whether the widespread uniform nuclear γ-H2AX (called pan-nuclear) pattern occurring upon intense replication stress (RS) is linked to DDR. Using a novel monoclonal antibody that binds exclusively to the phosphorylated C-terminus of H2AX, we demonstrate that H2AX phosphorylation is systematically pan-nuclear in cancer cells stressed with RS-inducing drugs just before they die. The pan-nuclear γ-H2AX pattern is abolished by inhibition of the DNA-PK kinase. Cell death induction of cancer cells treated with increasing combinations of replication and kinase (ATR and Chk1) inhibitory drugs was proportional to the appearance of pan-nuclear γ-H2AX pattern. Delivery of labeled anti-γ-H2AX Fabs in stressed cells demonstrated at a single cell level that pan-nuclear γ-H2AX formation precedes irreversible cell death. Moreover, we show that H2AX is not required for RS-induced cell death in HeLa cells. Thus, the nuclear-wide formation of γ-H2AX is an incident of RS-induced cell death and, thus, the pan nuclear H2AX pattern should be regarded as an indicator of lethal RS-inducing drug efficacy."],"journal":["Cancers"],"pubmed_title":["Uniform Widespread Nuclear Phosphorylation of Histone H2AX Is an Indicator of Lethal DNA Replication Stress."],"pmcid":["PMC6468890"],"funding_grant_id":["ERC-2013-340551, Birtoaction","Seed Money - 2018","Subvention-campagne 2016","340551"],"pubmed_authors":["Moeglin E","Desplancq D","Stoessel A","Conic S","Weiss E","Oulad-Abdelghani M","Chiper M","Vigneron M","Didier P","Tora L"],"additional_accession":[]},"is_claimable":false,"name":"Uniform Widespread Nuclear Phosphorylation of Histone H2AX Is an Indicator of Lethal DNA Replication Stress.","description":"Phosphorylated histone H2AX (γ-H2AX), a central player in the DNA damage response (DDR), serves as a biomarker of DNA double-strand break repair. Although DNA damage is generally visualized by the formation of γ-H2AX foci in injured nuclei, it is unclear whether the widespread uniform nuclear γ-H2AX (called pan-nuclear) pattern occurring upon intense replication stress (RS) is linked to DDR. Using a novel monoclonal antibody that binds exclusively to the phosphorylated C-terminus of H2AX, we demonstrate that H2AX phosphorylation is systematically pan-nuclear in cancer cells stressed with RS-inducing drugs just before they die. The pan-nuclear γ-H2AX pattern is abolished by inhibition of the DNA-PK kinase. Cell death induction of cancer cells treated with increasing combinations of replication and kinase (ATR and Chk1) inhibitory drugs was proportional to the appearance of pan-nuclear γ-H2AX pattern. Delivery of labeled anti-γ-H2AX Fabs in stressed cells demonstrated at a single cell level that pan-nuclear γ-H2AX formation precedes irreversible cell death. Moreover, we show that H2AX is not required for RS-induced cell death in HeLa cells. Thus, the nuclear-wide formation of γ-H2AX is an incident of RS-induced cell death and, thus, the pan nuclear H2AX pattern should be regarded as an indicator of lethal RS-inducing drug efficacy.","dates":{"release":"2019-01-01T00:00:00Z","publication":"2019 Mar","modification":"2025-04-19T21:56:41.748Z","creation":"2019-06-06T22:46:47Z"},"accession":"S-EPMC6468890","cross_references":{"pubmed":["30871194"],"doi":["10.3390/cancers11030355"]}}