Concerted regulation of ISWI by an autoinhibitory domain and the H4 N-terminal tail

Ludwigsen, Johanna; Pfennig, Sabrina; Singh, Ashish Kumar; Schindler, Christina; Harrer, Nadine; Forné, Ignasi; Zacharias, Martin; Mueller-Planitz, Felix

doi:10.7554/elife.21477

Cited by 30 publications

(32 citation statements)

References 55 publications

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“…The N terminus is separate from the chromodomains, and its inhibitory nature in the human CHD1 protein contrasts that of the yeast protein, for which the chromodomains have been reported to regulate its ATPase activity ( 36 , 37 ). Similar inhibitory domains in the N terminus of ISWI have been reported ( 36 , 38 ).…”

Section: Discussionsupporting

confidence: 85%

Human CHD1 is required for early DNA-damage signaling and is uniquely regulated by its N terminus

Zhou

Serafim

et al. 2018

Nucleic Acids Research

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CHD1 is a conserved chromatin remodeling enzyme required for development and linked to prostate cancer in adults, yet its role in human cells is poorly understood. Here, we show that targeted disruption of the CHD1 gene in human cells leads to a defect in early double-strand break (DSB) repair via homologous recombination (HR), resulting in hypersensitivity to ionizing radiation as well as PARP and PTEN inhibition. CHD1 knockout cells show reduced H2AX phosphorylation (γH2AX) and foci formation as well as impairments in CtIP recruitment to the damaged sites. Chromatin immunoprecipitation following a single DSB shows that the reduced levels of γH2AX accumulation at DSBs in CHD1-KO cells are due to both a global reduction in H2AX incorporation and poor retention of H2AX at the DSBs. We also identified a unique N-terminal region of CHD1 that inhibits the DNA binding, ATPase, and chromatin assembly and remodeling activities of CHD1. CHD1 lacking the N terminus was more active in rescuing the defects in γH2AX formation and CtIP recruitment in CHD1-KO cells than full-length CHD1, suggesting the N terminus is a negative regulator in cells. Our data point to a role for CHD1 in the DSB repair process and identify a novel regulatory region of the protein.

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Section: Discussionsupporting

confidence: 85%

Human CHD1 is required for early DNA-damage signaling and is uniquely regulated by its N terminus

Zhou

Serafim

et al. 2018

Nucleic Acids Research

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“…Both assays indicate that ALC1 is a monomer in vivo (compared to positive controls). Our data suggest that the C-terminal macrodomain of ALC1 packs against one or both of its ATPase lobes in the context of the full-length ALC1 protein, hinting at an intramolecular ''gating'' function of the ALC1 macrodomain, as described for the unrelated chromodomain of yCHD1 and the NTR domain of ISWI (Hauk et al, 2010;Ludwigsen et al, 2017).…”

Section: Modular Auto-inhibition In the Remodeler Alc1mentioning

confidence: 61%

“…Such mechanisms help ensure that remodelers are only active where and when needed. While the mechanisms through which the Chd1 and ISWI remodelers are regulated by nucleosomes have been explored (Clapier and Cairns, 2012;Hauk et al, 2010;Ludwigsen et al, 2017;Yan et al, 2016), less is known about how DNA damage triggers the activity of remodelers such as the PARP1-dependent ALC1 (Ahel et al, 2009;Gottschalk et al, 2012;, which massively decompacts chromatin upon DNA damage (Movie S1; Sellou et al, 2016). Considering ALC1's validated roles as an oncogene (ALC1 is amplified in several cancers and promotes metastases, proliferation, and pluripotency; Chen et al, 2010;Jiang et al, 2015;Kulkarni et al, 2013;Ma et al, 2008), understanding how PAR triggers ALC1 activity would advance our molecular understanding of how DNA damage impacts our genome, shed light on how a NAD + metabolite and nucleic acid triggers the activation of an oncogene, and reveal approaches that might allow us to target ALC1 therapeutically.…”

Section: Introductionmentioning

confidence: 99%

A Poly-ADP-Ribose Trigger Releases the Auto-Inhibition of a Chromatin Remodeling Oncogene

et al. 2017

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DNA damage triggers chromatin remodeling by mechanisms that are poorly understood. The oncogene and chromatin remodeler ALC1/CHD1L massively decompacts chromatin in vivo yet is inactive prior to DNA-damage-mediated PARP1 induction. We show that the interaction of the ALC1 macrodomain with the ATPase module mediates auto-inhibition. PARP1 activation suppresses this inhibitory interaction. Crucially, release from auto-inhibition requires a poly-ADP-ribose (PAR) binding macrodomain. We identify tri-ADP-ribose as a potent PAR-mimic and synthetic allosteric effector that abrogates ATPase-macrodomain interactions, promotes an ungated conformation, and activates the remodeler's ATPase. ALC1 fragments lacking the regulatory macrodomain relax chromatin in vivo without requiring PARP1 activation. Further, the ATPase restricts the macrodomain's interaction with PARP1 under non-DNA damage conditions. Somatic cancer mutants disrupt ALC1's auto-inhibition and activate chromatin remodeling. Our data show that the NAD-metabolite and nucleic acid PAR triggers ALC1 to drive chromatin relaxation. Modular allostery in this oncogene tightly controls its robust, DNA-damage-dependent activation.

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“…In this model, the human Acf1 N-terminus binds to extranucleosomal DNA in nucleosomes with long linker length, allowing the Snf2h (Isw2) catalytic subunit to engage the H4 tail. Snf2h engagement of the H4 tail relieves known autoinhibitory interactions 46,48 thereby activating the remodeling complex. When linker DNA length shortens, the N-terminus of Acf1 switches to binding the H4 tail, thus displacing the Snf2h catalytic subunit and inactivating the complex through autoinhibition.…”

Section: The Conserved Wac Domain Tethers Isw2 To Transcription Factomentioning

confidence: 99%

Basis of Specificity for a Conserved and Promiscuous Chromatin Remodeling Protein

Donovan

Crandall

Truong

et al. 2020

Preprint

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Eukaryotic genomes are organized dynamically through the repositioning of nucleosomes. Isw2 is an enzyme that has been previously defined as a genome-wide, non-specific nucleosome spacing factor. Here, we show that Isw2 instead acts as an obligately targeted nucleosome remodeler in vivo through physical interactions with sequence-specific factors. We demonstrate that Isw2recruiting factors use small and previously uncharacterized epitopes, which direct Isw2 activity through highly conserved acidic residues in the Isw2 accessory protein Itc1. This interaction orients Isw2 on target nucleosomes, allowing for precise nucleosome positioning at targeted loci. Finally, we show that these critical acidic residues have been lost in the Drosophila lineage, potentially explaining the inconsistently characterized function of Isw2-like proteins. Altogether, these data suggest an "interacting barrier model" where Isw2 interacts with a sequence-specific factor to accurately and reproducibly position a single, targeted nucleosome to define the precise border of phased chromatin arrays. Supervision, L.E.M. and J.N.M.; Project Administration, J.N.M.; Funding Acquisition, J.N.M.The authors declare no conflict of interest.Sequencing data sets can be accessed in the Gene Expression Omnibus with Accession Number GSE149804.

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Concerted regulation of ISWI by an autoinhibitory domain and the H4 N-terminal tail

Cited by 30 publications

References 55 publications

Human CHD1 is required for early DNA-damage signaling and is uniquely regulated by its N terminus

Human CHD1 is required for early DNA-damage signaling and is uniquely regulated by its N terminus

A Poly-ADP-Ribose Trigger Releases the Auto-Inhibition of a Chromatin Remodeling Oncogene

Basis of Specificity for a Conserved and Promiscuous Chromatin Remodeling Protein

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