Subunit Composition and Substrate Specificity of a MOF-containing Histone Acetyltransferase Distinct from the Male-specific Lethal (MSL) Complex

Cai, Yong; Jin, Jingji; Swanson, Selene K.; Cole, Michael; Choi, Seung Hyuk; Florens, Laurence; Washburn, Michael P.; Conaway, Joan Weliky; Conaway, Ronald C.

doi:10.1074/jbc.c109.087981

Cited by 217 publications

(248 citation statements)

References 37 publications

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“…So far, hMOF is known to be contained in two different complexes, MOF-MSL and MOF-MSL1v1 [15,34]. Both the complexes have acetyltransferase activity toward nucleosomal H4, but free hMOF barely showed any activity toward HeLa nucleosomes [35,36], even though MOF has been shown to be able to bind to the chromatin [37]. Our results showed that free hMOF acetylates itself in the MYST domain, and autoacetylation greatly decreased its binding to reconstituted nucleosomes or native HeLa nucleosomes.…”

Section: Discussionmentioning

confidence: 64%

“…First, certain deacetylases (for example SIRT1) may remove acetylation of hMOF and increase its interaction with the nucleosomal substrate ( Figure 9). Second, the well-studied proteins in different hMOF complexes, like MSL1/2/3 and MSL1v1 [35,36], may interfere with the autoacetylation of hMOF so as to facilitate targeting of hMOF to specific substrates, or meanwhile, stabilize its interaction with the substrates.…”

Section: Discussionmentioning

confidence: 99%

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Modulations of hMOF autoacetylation by SIRT1 regulate hMOF recruitment and activities on the chromatin

et al. 2011

Cell Res

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A wide variety of nuclear regulators and enzymes are subjected to acetylation of the lysine residue, which regulates different aspects of protein functions. The MYST family histone acetyltransferase, human ortholog of MOF (hMOF), plays critical roles in transcription activation by acetylating nucleosomal H4K16. In this study, we found that hMOF acetylates itself in vitro and in vivo, and the acetylation is restricted to the conserved MYST domain (C2HC zinc finger and HAT), of which the K274 residue is the major autoacetylation site. Furthermore, the class III histone deacetylase SIRT1 was found to interact with the MYST domain of hMOF through the deacetylase catalytic region and deacetylate autoacetylated hMOF. In vitro binding assays showed that non-acetylated hMOF robustly binds to nucleosomes while acetylation decreases the binding ability. In HeLa cells, the recruitment of hMOF to the chromatin increases in response to SIRT1 overexpression and decreases after knockdown of SIRT1. The acetylation mimic mutation K274Q apparently decreases the chromatin recruitment of hMOF as well as the global H4K16Ac level in HeLa cells. Finally, upon SIRT1 knockdown, hMOF recruitment to the gene body region of its target gene HoxA9 decreases, accompanied with decrease of H4K16Ac at the same region and repression of HoxA9 transcription. These results suggest a dynamic interplay between SIRT1 and hMOF in regulating H4K16 acetylation.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Modulations of hMOF autoacetylation by SIRT1 regulate hMOF recruitment and activities on the chromatin

et al. 2011

Cell Res

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“…4A, lanes 3-7, and Fig. S5) and VP16 fl (lanes [8][9][10][11][12][13][14][15][16][17][18][19][20]. Whereas, HCF-1 C sequences are more important for VP16 fl than VP16 ΔAD VIC formation (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…HCF-1 was initially identified as a human coactivator for immediate-early gene expression of herpes simplex virus (HSV) by forming a complex (VP16-induced complex, VIC) with the HSV protein VP16 and the cellular transcriptional regulator Oct-1 (1). HCF-1 regulates cell-cycle progression by mediating associations between DNA-binding transcription factors and chromatin modifying complexes (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”

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confidence: 99%

HCF-1 self-association via an interdigitated Fn3 structure facilitates transcriptional regulatory complex formation

Park

Lammers

Herr

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Host-cell factor 1 (HCF-1) is an unusual transcriptional regulator that undergoes a process of proteolytic maturation to generate N-(HCF-1 N ) and C-(HCF-1 C ) terminal subunits noncovalently associated via self-association sequence elements. Here, we present the crystal structure of the self-association sequence 1 (SAS1) including the adjacent C-terminal HCF-1 nuclear localization signal (NLS). SAS1 elements from each of the HCF-1 N and HCF-1 C subunits form an interdigitated fibronectin type 3 (Fn3) tandem repeat structure. We show that the C-terminal NLS recruited by the interdigitated SAS1 structure is required for effective formation of a transcriptional regulatory complex: the herpes simplex virus VP16-induced complex. Thus, HCF-1 N -HCF-1 C association via an integrated Fn3 structure permits an NLS to facilitate formation of a transcriptional regulatory complex.crystallography | chromatin | nuclear localization sequence H ost cell factor-1 (HCF-1; also known as HCFC1) is a metazoan transcriptional regulator. HCF-1 was initially identified as a human coactivator for immediate-early gene expression of herpes simplex virus (HSV) by forming a complex (VP16-induced complex, VIC) with the HSV protein VP16 and the cellular transcriptional regulator Oct-1 (1). HCF-1 regulates cell-cycle progression by mediating associations between DNA-binding transcription factors and chromatin modifying complexes (2-12).Many HCF-1 proteins, including all known vertebrate HCF-1s, undergo a process of proteolytic maturation. Thus, human HCF-1 is synthesized as a 2035-aa precursor, which is cleaved and modified by O-GlcNAC transferase (13) to generate HCF-1 N and HCF-1 C subunits possessing different roles in, for example, cell-cycle regulation (14). After cleavage, the two resulting HCF-1 N and HCF-1 C subunits remain noncovalently associated via two "selfassociation sequences" called SAS1 and SAS2: SAS1 is the primary association element and its sequence is conserved in HCF-1, whereas SAS2 is secondary, less well conserved, and not considered in this study (15).SAS1 is composed of a short 43-aa HCF-1 N segment called SAS1N and a 197-aa HCF-1 C segment called SAS1C (Fig. 1A). Wilson et al. (15) suggested that SAS1C has two tandem fibronectin type 3 (Fn3) repeat structures forming a binding site for the 43-aa SAS1N to promote HCF-1 N -HCF-1 C association.To understand the mechanism of HCF-1 self-association, we have determined the crystal structure of SAS1 with the neighboring nuclear localization signal (called here SAS1-NLS). Contrary to expectation, SAS1N and SAS1C together-not SAS1C aloneform an integrated tandem Fn3 structure. Furthermore, we show that the self-association tethers the basic NLS to the HCF-1 N Kelch domain to facilitate VP16-induced complex formation. ResultsCrystal Structure of the HCF-1 SAS1 Self-Association Domain. The SAS1-NLS crystal structure (Fig. 1B) was determined to 2.7 Å resolution using the Se single-wavelength anomalous dispersion (SAD) method (Table S1 and Fig. S1). Fig. S2 details schematically...

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“…6 The complex consists of several proteins, including KANSL1, KANSL2, KANSL3, WDR5, MCRS1, and PHF20, and the histone acetyltransferase KAT8. [7][8][9] The recurrent 17q21.31 deletion (hg19 chr17:g.43700000_ 44300000) contains several genes, including CRHR1 (OMIM *122561), STH (OMIM *607067), MAPT (OMIM *157140), and KANSL1 (OMIM *612452), and is flanked by extensive low copy repeats (LCRs) or segmental duplications. The locus is genomically complex with multiple structurally diverse haplotypes segregating in the human population.…”

Section: Introductionmentioning

confidence: 99%

The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant

et al. 2015

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The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.

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Subunit Composition and Substrate Specificity of a MOF-containing Histone Acetyltransferase Distinct from the Male-specific Lethal (MSL) Complex

Cited by 217 publications

References 37 publications

Modulations of hMOF autoacetylation by SIRT1 regulate hMOF recruitment and activities on the chromatin

Modulations of hMOF autoacetylation by SIRT1 regulate hMOF recruitment and activities on the chromatin

HCF-1 self-association via an interdigitated Fn3 structure facilitates transcriptional regulatory complex formation

The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant

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