UBR7 is a novel chromatin directed E3 ubiquitin ligase

UBR7 是一种新型染色质定向 E3 泛素连接酶

基本信息

批准号：
8770744
负责人：
Daniel Richard Foltz
金额：
$ 19.45万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8770744
关键词：
Accounting Address Affect Affinity Affinity Chromatography Amino Acid Motifs Arabidopsis Autistic Disorder Autoimmune Diseases Binding Biological Markers Biology Boxing Cell physiology Cells ChIP-seq Chromatin Couples Data Degradation Pathway Development Diagnosis Disease Environmental Risk Factor Epigenetic Process Etiology Exploratory/Developmental Grant Family Family member Fission Yeast Gene Dosage Gene Expression Gene Expression Regulation Gene Targeting Generations Genes Genetic Genetic Transcription Genome Goals Histone H3 Histones Human Individual Intention Lead Link Malignant Neoplasms Mediating Modeling Modification Mus Mutate Mutation NIH Program Announcements Outcome Pathway interactions Pattern Peptide Signal Sequences Plants Post-Translational Protein Processing Property Protein Binding Protein Family Proteins Reader Recruitment Activity Regulation Reporting Research Research Project Grants Role Sea Urchins Site Staging Structure Tail Tertiary Protein Structure Testing Therapeutic Transcriptional Regulation Ubiquitination Variant arginine methyltransferase autism spectrum disorder epigenetic variation exome gene function histone modification mutant nervous system disorder novel promoter protein complex protein degradation protein function public health relevance research study ubiquitin ligase ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Gene transcription is governed by the posttranslational modification of histones that recruit the effectors of gene transcription. The posttranslational modification of histones can result in short-term control of gene transcription o they can act as long-term epigenetic determinants of gene transcription that can faithfully transmit the activation status of a gene across many cellular generations. A recent large-scale exome screen identified a mutation in the gene UBR7 in a family with autism. UBR7 contains a UBR- box and therefore belongs to a family of proteins involved in the recognition and ubiquitination of proteins that contain an N-degron signal sequence. UBR7 is the most divergent of the seven family members and has no demonstrated affinity for N-degron containing proteins. UBR7 also contains a PHD domain immediately adjacent to the UBR-box which makes it unique from other UBR proteins. PHD domains are common in chromatin associated protein that binds to posttranslationally modified histone H3 amino terminal tails. The function of UBR7 and it role in autism are completely undefined. We hypothesize that UBR7 binds chromatin via its PHD domain and regulates transcription through ubiquitination of histone proteins. The mutation associated with autism lies between the UBR-Box and PHD domains. We expect that the autism-associated mutant will alter the function of the UBR-box, PHD domain or both, and result in altered gene expression that contributes to the development of autism. The experiments proposed with test the binding of UBR7 to modified histone H3 amino terminal tails, assess the E3 ligase activity of UBR7 and determine if the autism associated mutant affects these properties. We determine the genes regulated by UBR7 and compare their expression between cells containing wild-type and mutated UBR7. Together these experiments will provide the first mechanistic description of a new autism gene and characterize a unique chromatin associated protein that may couple posttranslational modification of histones to ubiquitinylation.

描述（由申请人提供）：基因转录受组蛋白翻译后修饰的控制，该组蛋白募集了基因转录的效应子。组蛋白的翻译后修饰可能导致对基因转录的短期控制，它们可以充当基因转录的长期表观遗传决定因素，可以忠实地将基因的激活状态跨越许多细胞世代。最近的大型外显屏屏幕确定了自闭症家庭中基因UBR7的突变。 UBR7包含一个UBR框，因此属于涉及包含N-Degron信号序列的蛋白质识别和泛素化的蛋白质家族。 UBR7是七个家庭成员中最不同的，并且对含有N-Degron的蛋白质没有证明的亲和力。 UBR7还包含一个与UBR-Box相邻的PHD域，这使其与其他UBR蛋白质独特。 PHD结构域在染色质蛋白中很常见，该蛋白与翻译后修饰的组蛋白H3氨基末端尾巴结合。 UBR7和IT在自闭症中的作用是完全不确定的。我们假设UBR7通过其PHD结构域结合染色质，并通过泛素化组蛋白来调节转录。与自闭症相关的突变位于UBR-Box和PHD域之间。我们预计自闭症相关的突变体将改变UBR-box，PHD结构域或两者兼而有之的功能，并导致基因表达改变，从而有助于自闭症的发展。通过测试UBR7与修饰的组蛋白H3氨基末端的结合提出的实验，评估UBR7的E3连接酶活性，并确定自闭症相关的突变体是否影响这些特性。我们确定由UBR7调节的基因，并比较它们在含有野生型和突变UBR7的细胞之间的表达。这些实验将共同提供新的自闭症基因的第一个机械描述，并表征独特的染色质蛋白，该蛋白可能将组蛋白的翻译后修饰与泛素化。