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Genetics and Biochemistry of a Murine Retroposon

鼠逆转录子的遗传学和生物化学

基本信息

批准号：
7646473
负责人：
SANDRA L MARTIN
金额：
$ 35.59万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7646473
关键词：
Abbreviations Address Aging Amino Acid Substitution Binding Biochemical Biochemistry Breast Chromosomal translocation Colon Carcinoma Congenital Abnormality DNA DNA Binding DNA Sequence Rearrangement Deposition Development Disease Elements Embryonic Development Event Evolution Exons Functional RNA Gametogenesis Gene Duplication Genes Genetic Genetic Recombination Genetic Transcription Genome Genomics Goals Hemophilia A Hereditary Disease Human Genome Hybrids In Vitro Insertional Mutagenesis Intercistronic Region Introns Kanamycin Kinase Lead Length Malignant Neoplasms Maps Messenger RNA Molecular Molecular Chaperones Movement Mus Muscular Dystrophies Mutation Nature Nuclear Nucleic Acid Binding Nucleic Acids ORF2 protein Open Reading Frames Phosphotransferase Gene Process Proteins Pseudogenes RNA RNA Binding RNA-Directed DNA Polymerase Reaction Research Personnel Retroposon Retrotransposition Reverse Transcription Ribonucleoproteins Ribosomes Role Series Short Interspersed Nucleotide Elements Somatic Cell Structure System Testing Time To specify Transcript Translations base design endonuclease homologous recombination in vitro Assay in vivo mammalian genome messenger ribonucleoprotein monomer novel particle polypeptide research study response

项目摘要

DESCRIPTION (provided by applicant): LINE-1 (Long Interspersed Nuclear Element-1, or L1) is a major dynamic force in the mammalian genome. Retrotransposition deposits the progeny of L1 throughout the genome, sometimes leading to gene disruption, modified expression of adjacent genes, and/or transduction of neighboring DNA. In addition, L1, as interspersed repetitive DNA, provides a substrate for homologous recombination of mispaired sequences, leading to gene duplication, deletion, chromosome translocation and, potentially, exon shuffling. Any 1 of the dynamic events caused by the presence and movement of L1 in the human genome can lead to disease; in fact, LINE-1 insertional mutagenesis has been found to be responsible for a wide variety of diseases including hemophilia and muscular dystrophy, as well as breast and colon cancer. Thus, it is extremely important to understand the details of the intermediates involved in retrotransposition and the mechanisms used to control their expression and movement in vivo. If the normal control mechanisms of L1 expression and retrotransposition become deranged either during development (gametogenesis or early embryogenesis) or in somatic cells in response to environmental insults or aging, movement and rearrangement of L1 sequences could be an instrumental component of the genetic instability responsible for genetic diseases, birth defects and cancers. Our long-range goal is to understand the retrotransposition process in detail, including the biochemical intermediates involved, as well as its control in genetic and evolutionary time. L1 retrotransposition begins with transcription of full-length, sense-strand L1 RNA and requires the 2 L1-encoded polypeptides acting in cis. The studies proposed here are specifically designed to: 1) Further elucidate the role of the L1-encoded ORF1 protein during retrotransposition by investigating the effects of mutations on retrotransposition activity, and on the nucleic acid binding and chaperone activities of the isolated ORF1 protein; 2) Determine the basis for the interaction between the ORF1 and ORF2 proteins, and provide new biochemical information about the structure and functions of the ORF2 protein; 3) Determine the molecular basis of translational control of the 2 L1-encoded proteins, and define the protein components associated with the L1RNA as it transitions from its function as the translation template to an assembled L1 retrotransposition machine.

描述（由申请人提供）：LINE-1（长分散核元件-1或L1）是哺乳动物基因组中的主要动力。反转录转座使L1的后代在整个基因组中沉积，有时导致基因破坏、相邻基因的修饰表达和/或相邻DNA的转导。此外，L1作为散布的重复DNA，为错配序列的同源重组提供了底物，导致基因复制、缺失、染色体易位和潜在的外显子改组。由人类基因组中L1的存在和移动引起的任何一个动态事件都可能导致疾病;事实上，LINE-1插入突变已被发现是多种疾病的原因，包括血友病和肌营养不良症，以及乳腺癌和结肠癌。因此，了解反转录转座中涉及的中间体的细节以及用于控制它们在体内表达和运动的机制是极其重要的。如果L1表达和反转录转座的正常控制机制在发育过程中（配子发生或早期胚胎发生）或体细胞中响应于环境损伤或衰老而变得紊乱，则L1序列的运动和重排可能是导致遗传疾病、出生缺陷和癌症的遗传不稳定性的重要组成部分。我们的长期目标是详细了解反转录转座过程，包括所涉及的生化中间体，以及它在遗传和进化时间中的控制。L1反转录转座开始于全长有义链L1 RNA的转录，并需要2个L1编码的多肽顺式作用。1）通过研究突变对反转录转座活性的影响，以及对分离的ORF 1蛋白的核酸结合和分子伴侣活性的影响，进一步阐明L1编码的ORF 1蛋白在反转录转座过程中的作用; 2）确定ORF 1和ORF 2蛋白之间相互作用的基础，并提供了有关ORF 2蛋白结构和功能的新的生化信息; 3）确定2种L1编码蛋白的翻译控制的分子基础，并定义与L1 RNA相关的蛋白质组分，因为它从其作为翻译模板的功能转变为组装的L1反转录转座机器。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The ORF1 protein encoded by LINE-1: structure and function during L1 retrotransposition.

DOI：
10.1155/jbb/2006/45621
发表时间：
2006
期刊：
JOURNAL OF BIOMEDICINE AND BIOTECHNOLOGY
影响因子：
0
作者：
Martin, Sandra L.
通讯作者：
Martin, Sandra L.

Mouse maelstrom, a component of nuage, is essential for spermatogenesis and transposon repression in meiosis.

DOI：
10.1016/j.devcel.2008.05.015
发表时间：
2008-08
期刊：
DEVELOPMENTAL CELL
影响因子：
11.8
作者：
Soper, Sarah F. C.;van der Heijden, Godfried W.;Hardiman, Tara C.;Goodheart, Mary;Martin, Sandra L.;de Boer, Peter;Bortvin, Alex
通讯作者：
Bortvin, Alex

A single amino acid substitution in ORF1 dramatically decreases L1 retrotransposition and provides insight into nucleic acid chaperone activity.

DOI：
10.1093/nar/gkn554
发表时间：
2008-10
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Martin SL;Bushman D;Wang F;Li PW;Walker A;Cummiskey J;Branciforte D;Williams MC
通讯作者：
Williams MC

A role for retrotransposon LINE-1 in fetal oocyte attrition in mice.

DOI：
10.1016/j.devcel.2014.04.027
发表时间：
2014-06-09
期刊：
DEVELOPMENTAL CELL
影响因子：
11.8
作者：
Malki, Safia;van der Heijden, Godfried W.;O'Donnell, Kathryn A.;Martin, Sandra L.;Bortvin, Alex
通讯作者：
Bortvin, Alex

Functional reverse transcriptases encoded by A-type mouse LINE-1: defining the minimal domain by deletion analysis.

A 型小鼠 LINE-1 编码的功能性逆转录酶：通过删除分析定义最小结构域。