Repression of Six3 by a corepressor regulates rhodopsin expression

Manavathi, Bramanandam; Peng, Shaohua; Rayala, Suresh K.; Talukder, Amjad H.; Wang, Minhua H.; Wang, Rui An; Balasenthil, Seetharaman; Agarwal, Neeraj; Frishman, Laura J.; Kumar, Rakesh

doi:10.1073/pnas.0705878104

Cited by 63 publications

(81 citation statements)

References 23 publications

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“…In this context, because the exact p53 binding region for COP1 remains unknown, we first mapped the regions of p53 involved in binding COP1 using a series of GSTp53 fusion proteins (38). Results showed that 35 S-labeled, in vitro-translated COP1 binds to the DNA binding domain (amino acids 92-160) and the C-terminal domain (amino acids 318 -393) of p53 ( Fig. 4E and supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

“…1B). To determine whether MTA1 directly binds to p53, we next performed in vitro GST pull-down assays using 35 S-labeled, in vitro-translated MTA1 protein and full-length GSTp53 fusion protein (38), and found that 35 S-labeled MTA1 strongly bound to GST-p53 protein (supplemental Fig. S1A, lane 4).…”

Section: Resultsmentioning

confidence: 99%

“…S1A, lane 4). To further identify the regions of p53 involved in binding MTA1, we used a series of GST-p53 fusion proteins (38) and analyzed their ability to bind to 35 S-labeled, in vitro-translated, full-length MTA1. We found that the observed MTA1 binding to p53 was confined to amino acids 318 -393 in the C terminus ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…ϩ/ϩ and MTA1 Ϫ/Ϫ MEFs were generated in our laboratory from embryos at day 9 of development by using a standard protocol (35). Stable clones of MTA1…”

Section: Methodsmentioning

confidence: 99%

“…One day later, the cells were incubated in Dulbecco's modified Eagle's medium (no L-glutamine, sodium pyruvate, L-methionine, or L-cystine) (Invitrogen, Cat. 21013-024) supplemented with 5% dialyzed fetal bovine serum, 1ϫ L-glutamine, 1ϫ sodium pyruvate (Invitrogen), and 100 Ci of EXPRE 35 S 35 S protein labeling mix (11 mCi/ml, PerkinElmer, Waltham, MA) for 1-2 h. The medium was replaced with Dulbecco's modified Eagle's medium containing 5% dialyzed fetal calf serum, 1ϫ L-glutamine, 1ϫ sodium pyruvate, 2 mM L-methionine, and 2 mM L-cystine (Sigma). At timed intervals during the chase period, cells lysates were prepared in Nonidet P-40 lysis buffer (50 mM Tris-HCl, pH 8, 150 mM NaCl, 0.5% Nonidet P-40, 10% glycerol, 2 mM MgCl 2 , and1 mM EDTA) and immunoprecipitated using the indicated antibodies.…”

Section: ϫ/ϫmentioning

confidence: 99%

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MTA1 Coregulator Regulates p53 Stability and Function

Reddy

Pakala

et al. 2009

Journal of Biological Chemistry

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Although metastasis-associated protein 1 (MTA1) has recently been shown as a DNA damage responsive protein, the underlying mechanism for its role in DNA double-strand break (DSB) repair remains unknown. Here, we show that MTA1 controls p53 stability through inhibiting its ubiquitination by E3 ubiquitin ligases mouse double minute 2 (Mdm2) and constitutive photomorphogenic protein 1 (COP1). The underlying mechanisms involve the ability of MTA1 to compete with COP1 to bind to p53 and/or to destabilize COP1 and Mdm2. Consequently, MTA1 regulates the p53-dependent transcription of p53R2, a direct p53 target gene for supplying nucleotides to repair damaged DNA. Depletion of MTA1 impairs p53-dependent p53R2 transcription and compromises DNA repair. Interestingly, these events could be reversed by MTA1 reintroduction, indicating that MTA1 interjects into the p53-dependent DNA repair. Given the fact that MTA1 is widely up-regulated in human cancers, these findings in conjunction with our earlier finding of a crucial role of MTA1 in DSB repair suggest an inherent role of the MTA1-p53-p53R2 pathway in DNA damage response in cancer cells.The p53 tumor suppressor is a central component of cellular mechanisms that respond to DNA damage signals to preserve genomic integrity (1, 2). Under physiological conditions, p53 is tightly regulated and normally maintained at low levels by the action of several RING finger E3 ubiquitin ligases, including constitutive photomorphogenic protein 1 (COP1) (3), mouse double minute 2 (Mdm2) (4, 5), and p53-induced protein with a RING H2 domain (Pirh2) (6). All of these ligases are transcriptionally stimulated by the p53 protein and in turn, target p53 for the ubiquitin-dependent proteolysis, thereby creating tight negative feedback loops for controlling p53 protein stability (7). Accordingly, disruption of these autoregulatory feedback loops is a pivotal event for the activation of p53 in response to various genotoxic stresses (8, 9). Following DNA damage, p53 protein is stabilized and activated through post-translational modifications, resulting in a controlled activation of a series of downstream target genes that mediate its functions (10 -12). In addition to its important functions in cell cycle arrest and apoptosis (2, 12), the p53 protein plays a critical role in regulating DNA repair caused by various genotoxic stresses (13-17). Loss of p53 function leads to decreased repair of damaged DNA and is reflected by increased sensitivity to DNA damage agents. Therefore, blocking the p53-induced DNA repair could prove to be an efficient approach to enhance the efficacy of DNA-damaging agents (18).Recently, numerous potential mechanisms have been described as to how p53 functions to regulate DNA repair. p53 directly associates with TFIIH, a nucleotide excision repair component (19) and transactivates genes implicated in DNA repair, such as p53R2, a newly identified subunit of ribonucleotide reductase (20, 21). The ability of p53R2 to supply nucleotides for repairing DNA damage requires the presen...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…ϩ/ϩ and MTA1 Ϫ/Ϫ MEFs were generated in our laboratory from embryos at day 9 of development by using a standard protocol (35). Stable clones of MTA1…”

Section: Methodsmentioning

confidence: 99%

Section: ϫ/ϫmentioning

confidence: 99%

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MTA1 Coregulator Regulates p53 Stability and Function

Reddy

Pakala

et al. 2009

Journal of Biological Chemistry

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The NuRD complex and macrocephaly associated neurodevelopmental disorders

Pierson

Otero

Grand

et al. 2019

American J of Med Genetics Pt C

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The nucleosome remodeling and deacetylase (NuRD) complex is a major regulator of gene expression involved in pluripotency, lineage commitment, and corticogenesis. This important complex is composed of seven different proteins, with mutations in CHD3, CHD4, and GATAD2B being associated with neurodevelopmental disorders presenting with macrocephaly and intellectual disability similar to other overgrowth and intellectual disability (OGID) syndromes. Pathogenic variants in CHD3 and CHD4 primarily involve disruption of enzymatic function. GATAD2B variants include loss‐of‐function mutations that alter protein dosage and missense variants that involve either of two conserved domains (CR1 and CR2) known to interact with other NuRD proteins. In addition to macrocephaly and intellectual disability, CHD3 variants are associated with inguinal hernias and apraxia of speech; whereas CHD4 variants are associated with skeletal anomalies, deafness, and cardiac defects. GATAD2B‐associated neurodevelopmental disorder (GAND) has phenotypic overlap with both of these disorders. Of note, structural models of NuRD indicate that CHD3 and CHD4 require direct contact with the GATAD2B‐CR2 domain to interact with the rest of the complex. Therefore, the phenotypic overlaps of CHD3‐ and CHD4‐related disorders with GAND are consistent with a loss in the ability of GATAD2B to recruit CHD3 or CHD4 to the complex. The shared features of these neurodevelopmental disorders may represent a new class of OGID syndrome: the NuRDopathies.

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Identification of a conserved cis‐regulatory element controlling mid‐diencephalic expression of mouse Six3

Lee

Yoon

Lam

et al. 2017

Genesis

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The sine oculis homeobox protein Six3 plays pivotal roles in the development of the brain and craniofacial structures. In humans, SIX3 haploinsufficiency results in holoprosencephaly, a defect in anterior midline formation. Although much is known about the evolutionarily conserved functions of Six3, the regulatory mechanism responsible for the expression pattern of Six3 remains relatively unexplored. To understand how the transcription of Six3 is controlled during embryogenesis, we screened ∼300 kb of genomic DNA encompassing the Six3 locus for cis-acting regulatory elements capable of directing reporter gene expression to sites of Six3 transcription in transgenic mouse embryos. We identified a novel enhancer element, whose activity recapitulates endogenous Six3 expression in the ventral midbrain, pretectum, and thalamus. Cross-species comparisons revealed that this Six3 brain enhancer is functionally conserved in other vertebrates. We also showed that normal Six3 transcription in the ventral midbrain and pretectum is dependent on Ascl1, a basic helix-loop-helix proneural factor. Moreover, loss of Ascl1 resulted in downregulation of the Six3 brain enhancer activity, emphasizing its unique role in regulating Six3 expression in the developing brain.

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Repression of Six3 by a corepressor regulates rhodopsin expression

Cited by 63 publications

References 23 publications

MTA1 Coregulator Regulates p53 Stability and Function

MTA1 Coregulator Regulates p53 Stability and Function

The NuRD complex and macrocephaly associated neurodevelopmental disorders

Identification of a conserved cis‐regulatory element controlling mid‐diencephalic expression of mouse Six3

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