SMARCAD1 is an ATP-dependent stimulator of nucleosomal H2A acetylation via CBP, resulting in transcriptional regulation

Doiguchi, Masamichi; Nakagawa, Takeya; Imamura, Yuko; Yoneda, Mitsuhiro; Higashi, Miki; Kubota, Kazuishi; Yamashita, Satoshi; Asahara, Hiroshi; Iida, Midori; Fujii, Satoshi; Ikura, Tsuyoshi; Liu, Ziying; Nandu, Tulip; Kraus, W. Lee; Ueda, Hitoshi; Ito, Takashi

doi:10.1038/srep20179

Cited by 26 publications

(23 citation statements)

References 52 publications

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“…Depletion of this enzyme results in an open chromatin conformation in normally transcriptionally repressed regions and can affect gene expression, suggesting that SMARCAD1 ensures correct chromatin structure of silent domains. SMARCAD1 can also activate transcription together with co-activator p300/CBP (CREB-binding protein), and interactions with the transcription machinery have recently been reported in S. pombe (20,21). In addition, SMARCAD1 is involved in double-strand break repair (22).…”

Section: Chromatin In Embryonic Stem Cells (Escs) Differs Markedly Frmentioning

confidence: 99%

The CUE1 domain of the SNF2-like chromatin remodeler SMARCAD1 mediates its association with KRAB-associated protein 1 (KAP1) and KAP1 target genes

Ding

Bergmaier

Sachs

et al. 2018

Journal of Biological Chemistry

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Chromatin in embryonic stem cells (ESCs) differs markedly from that in somatic cells, with ESCs exhibiting a more open chromatin configuration. Accordingly, ATP-dependent chromatin remodeling complexes are important regulators of ESC homeostasis. Depletion of the remodeler SMARCAD1, an ATPase of the SNF2 family, has been shown to affect stem cell state, but the mechanistic explanation for this effect is unknown. Here, we set out to gain further insights into the function of SMARCAD1 in mouse ESCs. We identified KRAB-associated protein 1 (KAP1) as the stoichiometric binding partner of SMARCAD1 in ESCs. We found that this interaction occurs on chromatin and that SMARCAD1 binds to different classes of KAP1 target genes, including zinc finger protein (ZFP) and imprinted genes. We also found that the RING B-box coiled-coil (RBCC) domain in KAP1 and the proximal coupling of ubiquitin conjugation to ER degradation (CUE) domain in SMARCAD1 mediate their direct interaction. Of note, retention of SMARCAD1 in the nucleus depended on KAP1 in both mouse ESCs and human somatic cells. Mutations in the CUE1 domain of SMARCAD1 perturbed the binding to KAP1 and Accordingly, an intact CUE1 domain was required for tethering this remodeler to the nucleus. Moreover, mutation of the CUE1 domain compromised SMARCAD1 binding to KAP1 target genes. Taken together, our results reveal a mechanism that localizes SMARCAD1 to genomic sites through the interaction of SMARCAD1's CUE1 motif with KAP1.

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Section: Chromatin In Embryonic Stem Cells (Escs) Differs Markedly Frmentioning

confidence: 99%

The CUE1 domain of the SNF2-like chromatin remodeler SMARCAD1 mediates its association with KRAB-associated protein 1 (KAP1) and KAP1 target genes

Ding

Bergmaier

Sachs

et al. 2018

Journal of Biological Chemistry

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“…The Smarcad1/Etl1/Fun30 family of chromatin remodeling factors is one of the most highly conserved families, found from fission (Fft1-3) and budding yeast (Fun30) to mouse (Smarcad1) and human (SMARCAD1), and is defined by the presence of CUE-domains in addition to the helicase-like domains [5]. Smarcad1 and its homologs have roles in gene regulation including gene silencing [5][6][7][8][9], heterochromatin maintenance [10,11], genome organization [12,13], and DNA repair [14,15]. A mutation in a skin-specific isoform of SMARCAD1 in humans causes adermatoglyphia (the loss of finger prints) and Basan syndrome, which affects skin integrity [16][17][18].…”

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confidence: 99%

Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium

et al. 2020

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Background: How intestinal epithelial cells interact with the microbiota and how this is regulated at the gene expression level are critical questions. Smarcad1 is a conserved chromatin remodeling factor with a poorly understood tissue function. As this factor is highly expressed in the stem and proliferative zones of the intestinal epithelium, we explore its role in this tissue. Results: Specific deletion of Smarcad1 in the mouse intestinal epithelium leads to colitis resistance and substantial changes in gene expression, including a striking increase of expression of several genes linked to innate immunity. Absence of Smarcad1 leads to changes in chromatin accessibility and significant changes in histone H3K9me3 over many sites, including genes that are differentially regulated upon Smarcad1 deletion. We identify candidate members of the gut microbiome that elicit a Smarcad1-dependent colitis response, including members of the poorly understood TM7 phylum. Conclusions: Our study sheds light onto the role of the chromatin remodeling machinery in intestinal epithelial cells in the colitis response and shows how a highly conserved chromatin remodeling factor has a distinct role in anti-microbial defense. This work highlights the importance of the intestinal epithelium in the colitis response and the potential of microbial species as pharmacological and probiotic targets in the context of inflammatory diseases. Background The intestinal epithelium is a highly dynamic tissue that is constantly renewed within a few days, driven by intestinal stem cells that reside at the base of intestinal crypts [1, 2]. Intestinal stem cells and their derivatives express many factors involved in DNA replication, DNA repair, chromatin packaging, and chromatin remodeling, including ATP-dependent remodeling factors [3]. The roles of these factors in genomic and epigenomic stability of this tissue are likely of great importance. Understanding epithelial biology is complicated by the fact that this tissue is in close proximity to the gut microbiota, which normally is either innocuous or even beneficial to the host, but can become pathogenic. How intestinal epithelial cells interact with the host immune system and the microbiota and how this is regulated at the gene expression level are critical questions.

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“…It was shown that the Fun30 (function unknown now 30) protein, which is a member of Swi2/Snf2 (switch/sucrose non-fermentable) family of proteins involved in chromatin remodeling, can facilitate the action of DNA2 in end resection by overcoming inhibiting effects induced by Rad9, which otherwise create a barrier for the resection [ 92 ]. The potential human homologue of Fun30 is already presented SMARCAD1, which was shown to be involved in end resection and colocalize with DSB repair markers, including γH2AX [ 73 , 93 ].…”

Section: Dna Damage Responsementioning

confidence: 99%

DNA2—An Important Player in DNA Damage Response or Just Another DNA Maintenance Protein?

Pawłowska

Szczepańska

Błasiak

2017

IJMS

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The human DNA2 (DNA replication helicase/nuclease 2) protein is expressed in both the nucleus and mitochondria, where it displays ATPase-dependent nuclease and helicase activities. DNA2 plays an important role in the removing of long flaps in DNA replication and long-patch base excision repair (LP-BER), interacting with the replication protein A (RPA) and the flap endonuclease 1 (FEN1). DNA2 can promote the restart of arrested replication fork along with Werner syndrome ATP-dependent helicase (WRN) and Bloom syndrome protein (BLM). In mitochondria, DNA2 can facilitate primer removal during strand-displacement replication. DNA2 is involved in DNA double strand (DSB) repair, in which it is complexed with BLM, RPA and MRN for DNA strand resection required for homologous recombination repair. DNA2 can be a major protein involved in the repair of complex DNA damage containing a DSB and a 5′ adduct resulting from a chemical group bound to DNA 5′ ends, created by ionizing radiation and several anticancer drugs, including etoposide, mitoxantrone and some anthracyclines. The role of DNA2 in telomere end maintenance and cell cycle regulation suggests its more general role in keeping genomic stability, which is impaired in cancer. Therefore DNA2 can be an attractive target in cancer therapy. This is supported by enhanced expression of DNA2 in many cancer cell lines with oncogene activation and premalignant cells. Therefore, DNA2 can be considered as a potential marker, useful in cancer therapy. DNA2, along with PARP1 inhibition, may be considered as a potential target for inducing synthetic lethality, a concept of killing tumor cells by targeting two essential genes.

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SMARCAD1 is an ATP-dependent stimulator of nucleosomal H2A acetylation via CBP, resulting in transcriptional regulation

Cited by 26 publications

References 52 publications

The CUE1 domain of the SNF2-like chromatin remodeler SMARCAD1 mediates its association with KRAB-associated protein 1 (KAP1) and KAP1 target genes

The CUE1 domain of the SNF2-like chromatin remodeler SMARCAD1 mediates its association with KRAB-associated protein 1 (KAP1) and KAP1 target genes

Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium

DNA2—An Important Player in DNA Damage Response or Just Another DNA Maintenance Protein?

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