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，组蛋白招募基因转录的效应子。组蛋白的翻译后修饰可以导致基因转录的短期控制，或者它们可以作为基因转录的长期表观遗传决定因素，可以在许多细胞代中忠实地传递基因的激活状态。最近的一项大规模外显子组筛查发现，一个自闭症家庭的 UBR7 基因存在突变。 UBR7 含有一个 UBR- 盒，因此属于参与识别和泛素化含有 N-降解决定子信号序列的蛋白质的蛋白质家族。 UBR7 是七个家族成员中差异最大的一个，并且没有表现出对含有 N-降解决定子的蛋白质的亲和力。 UBR7 还包含一个紧邻 UBR-box 的 PHD 结构域，这使其与其他 UBR 蛋白不同。 PHD 结构域在染色质相关蛋白中很常见，可与翻译后修饰的组蛋白 H3 氨基末端尾部结合。 UBR7 的功能及其在自闭症中的作用完全未明确。我们假设 UBR7 通过其 PHD 结构域结合染色质，并通过组蛋白泛素化调节转录。与自闭症相关的突变位于 UBR-Box 和 PHD 域之间。我们预计与自闭症相关的突变体将改变 UBR 盒、PHD 结构域或两者的功能，并导致基因表达改变，从而导致自闭症的发展。建议的实验测试 UBR7 与修饰的组蛋白 H3 氨基末端尾部的结合，评估 UBR7 的 E3 连接酶活性，并确定自闭症相关突变体是否影响这些特性。我们确定了 UBR7 调控的基因，并比较了它们在含有野生型和突变型 UBR7 的细胞之间的表达。这些实验将共同提供对新自闭症基因的第一个机制描述，并表征一种独特的染色质相关蛋白，该蛋白可能将组蛋白的翻译后修饰与泛素化结合起来。