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Title: A tail-based mechanism drives nucleosome demethylation by the LSD2/NPAC multimeric complex
Authors: Marabelli, Chiara
Marrocco, Biagina
Pilotto, Simona
Chittori, Sagar
Picaud, Sarah
Marchese, Sara
Ciossani, Giuseppe
Forneris, Federico
Filippakopoulos, Panagis
Schoehn, Guy
Rhodes, Daniela
Subramaniam, Sriram
Mattevi, Andrea
Keywords: Histone Demethylation
Cryoelectron Microscopy
DRNTU::Science::Biological sciences
Issue Date: 2019
Source: Marabelli, C., Marrocco, B., Pilotto, S., Chittori, S., Picaud, S., Marchese, S., . . . Mattevi, A. (2019). A tail-based mechanism drives nucleosome demethylation by the LSD2/NPAC multimeric complex. Cell Reports, 27(2), 387-399. doi:10.1016/j.celrep.2019.03.061
Series/Report no.: Cell Reports
Abstract: LSD1 and LSD2 are homologous histone demethylases with opposite biological outcomes related to chromatin silencing and transcription elongation, respectively. Unlike LSD1, LSD2 nucleosome-demethylase activity relies on a specific linker peptide from the multidomain protein NPAC. We used single-particle cryoelectron microscopy (cryo-EM), in combination with kinetic and mutational analysis, to analyze the mechanisms underlying the function of the human LSD2/NPAC-linker/nucleosome complex. Weak interactions between LSD2 and DNA enable multiple binding modes for the association of the demethylase to the nucleosome. The demethylase thereby captures mono- and dimethyl Lys4 of the H3 tail to afford histone demethylation. Our studies also establish that the dehydrogenase domain of NPAC serves as a catalytically inert oligomerization module. While LSD1/CoREST forms a nucleosome docking platform at silenced gene promoters, LSD2/NPAC is a multifunctional enzyme complex with flexible linkers, tailored for rapid chromatin modification, in conjunction with the advance of the RNA polymerase on actively transcribed genes.
ISSN: 2211-1247
DOI: 10.1016/j.celrep.2019.03.061
Rights: © 2019 The Author(s). This is an open access article under the CC BY-NC-ND license (
Fulltext Permission: open
Fulltext Availability: With Fulltext
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