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Ligase III regulates survival from crisis induced by gradual telomere shortening

连接酶 III 调节端粒逐渐缩短引起的危机中的生存

基本信息

批准号：
9114537
负责人：
ERIC A HENDRICKSON
金额：
$ 33.52万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9114537
关键词：
Address Affect Aging Applications Grants Area Award Belief Binding Biological Models Biology Cancer Biology Cell Aging Cell Death Cell Line Cell physiology Cells Chromosomal translocation Chromosomes DNA DNA Double Strand Break DNA Repair DNA ligase III Data Deposition Disease Double Strand Break Repair Dyskeratosis Congenita Event Gene Amplification Gene Targeting Genes Genetic Genome Genomic Instability Health Histones Human Human Cell Line Investigation Knock-out Knowledge Laboratories Lead Ligase Maintenance Malignant Neoplasms Mediating Medicine Modeling Mus Mutation Nobel Prize Nonhomologous DNA End Joining Null Lymphocytes Pancytopenia Pathway interactions Physiology Play Poly(ADP-ribose) Polymerases Predisposition Process Production Proliferating Regulation Role Sister Chromatid Somatic Cell Structure Syndrome System TP53 gene Technology Telomerase Telomere Maintenance Telomere Shortening Testing Variant Work XRCC1 gene base cell age cell transformation chromatin remodeling conditional mutant deep field survey genome-wide genome-wide analysis homologous recombination insight loss of function loss of function mutation nondeletion type alpha-thalassemia/mental retardation syndrome prevent progenitor response senescence single molecule telomere tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): We propose to investigate the mechanism(s) that regulate a cell's ability to escape from the crisis caused by gradual telomere shortening. In particular, we will define the roles that the i) A-NHEJ (alternative-non- homologous end joining) pathway of DNA DSB (double-strand break) repair as well as the ii) chromatin remodeling gene, ATRX (alpha thalassemia/mental retardation syndrome, X-linked), play in this process. As normal human cells age, their telomeres gradually shorten. When the telomeres shorten significantly, the cell undergoes senescence, which is a naturally-occurring, non-proliferative barrier to cancer. If, however, a cell should suffer a transforming mutation, it can by-pass senescence and continue to proliferate until its telomeres become so short that they are non-functional. The resulting lack of end protection triggers "crisis", a state that is highlighted by genomic instability as chromosomes engage in breakage:fusion:bridging cycles that almost invariably result in the death of the cell. On rare occasions a cell can reestablish its telomeres and stabilize its genome. Such cells are said to be immortalized and it is likely that they are the progenitors of most human cancers. That the (dys)regulation of telomere maintenance is also associated with aging, immortalization, and tumorigenesis in other experimental systems adds confidence to the belief that these issues are conserved and important. Here, we demonstrate that the genes LIGIII (DNA ligase III) and PARP1 {poly(ADP) ribose polymerase 1} are required for human cells to survive the crisis induced by gradual telomere shortening. LIGIII and PARP1 function in the A-NHEJ branch of DNA DSB repair. We hypothesize that it is the absence of A- NHEJ that results in the death of cells undergoing crisis and we propose to i) use structure:function approaches to define the molecular interactions required for the process, ii) identify other genes involved in crisis survival using directed approaches and genome-wide screens and iii) begin to test models for how LIGIII might mechanistically control this process. In addition, we describe our preliminary data demonstrating that ATRX is a crucial regulator of ALT (alternative lengthening of telomeres) and we describe an experimental system in which we can study the genesis of ALT. In all of these approaches we utilize the strengths of the Hendrickson and Baird laboratories. The Hendrickson laboratory excels at the technology of gene targeting to study the impact of loss-of-function mutations of genes (LIGIII, PARP1 and ATRX in this instance) on telomere maintenance. The use of gene targeting provides a facile experimental system in which null, hypomorphic, and/or conditional mutations can be introduced with rapidity into human somatic cells. The Baird laboratory is the world's leader in analyzing telomere fusion events in human cells undergoing crisis. Their ability to characterize the dynamics of single telomeric ends has provided the field's deepest understanding of the mechanism of telomere fusions in human cells. In summary, our proposed studies impact on DNA repair and telomere maintenance and the importance of understanding these processes for cancer biology is clear.