biostudies-literatureMamontova VDeutsche ForschungsgemeinschaftEuropean Research CouncilGerman Cancer AidHelmholtz Association915-930https://www.ebi.ac.uk/biostudies/studies/S-EPMC11535147biostudies-literatureUnknown38(17-20)Long noncoding (lnc)RNAs emerge as regulators of genome stability. The nuclear-enriched abundant transcript 1 (NEAT1) is overexpressed in many tumors and is responsive to genotoxic stress. However, the mechanism that links NEAT1 to DNA damage response (DDR) is unclear. Here, we investigate the expression, modification, localization, and structure of NEAT1 in response to DNA double-strand breaks (DSBs). DNA damage increases the levels and N6-methyladenosine (m⁶A) marks on NEAT1, which promotes alterations in NEAT1 structure, accumulation of hypermethylated NEAT1 at promoter-associated DSBs, and DSB signaling. The depletion of NEAT1 impairs DSB focus formation and elevates DNA damage. The genome-protective role of NEAT1 is mediated by the RNA methyltransferase 3 (METTL3) and involGenes & developmentNEAT1 promotes genome stability via m⁶A methylation-dependent regulation of CHD4.PMC11535147VH-NG-13478606100-NG110109694870114538SENATR 101096948449501615Gribling-Burrer ASMamontova VEilers MTrifault BBurger KBoten LBohn PAde CPSolvie DPreckwinkel PGutschner TGallant PPapadopoulos DSmyth RPfalseNEAT1 promotes genome stability via m⁶A methylation-dependent regulation of CHD4.Long noncoding (lnc)RNAs emerge as regulators of genome stability. The nuclear-enriched abundant transcript 1 (NEAT1) is overexpressed in many tumors and is responsive to genotoxic stress. However, the mechanism that links NEAT1 to DNA damage response (DDR) is unclear. Here, we investigate the expression, modification, localization, and structure of NEAT1 in response to DNA double-strand breaks (DSBs). DNA damage increases the levels and N6-methyladenosine (m⁶A) marks on NEAT1, which promotes alterations in NEAT1 structure, accumulation of hypermethylated NEAT1 at promoter-associated DSBs, and DSB signaling. The depletion of NEAT1 impairs DSB focus formation and elevates DNA damage. The genome-protective role of NEAT1 is mediated by the RNA methyltransferase 3 (METTL3) and invol2024-01-01T00:00:00Z2024 Oct2026-06-02T04:34:04.579Z2025-04-04T23:32:56.769ZS-EPMC115351473936277610.1101/gad.351913.124