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DNA repair pathway choice mediates somatic cell reprogramming

DNA修复途径选择介导体细胞重编程

基本信息

批准号：
10249291
负责人：
Dieter Meinrad Egli
金额：
$ 46.71万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10249291
关键词：
Affect Aneuploidy BRCA1 gene Basic Science Biological Assay Cell Cycle Cell Cycle Progression Cell Line Cell Therapy Cells Characteristics Competence DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway DNA biosynthesis DNA replication fork Data Development Double Strand Break Repair Frequencies G2 Phase Generations Genetic Transcription Genome Genome Stability Genomic Instability Genomics Impairment Laboratories Lead Location Maps Mediating Mitosis Molecular Mus Mutation Nonhomologous DNA End Joining Optics Pathway interactions Pluripotent Stem Cells Repetitive Sequence Research Role S Phase Signal Transduction Site Somatic Cell Structure System TP53 gene Techniques cell type genome integrity homologous recombination improved induced pluripotent stem cell mutant next generation sequencing nuclear transfer overexpression p53-binding protein 1 repaired senescence somatic cell nuclear transfer stem cells whole genome

项目摘要

Project Summary Reprogramming is the conversion of a somatic cell to a pluripotent stem cell. This technique is now routinely used in laboratories around the world, but the vast majority of reprogrammed stem cell lines are not developmentally fully competent, compromising their utility in research and therapy. Reprogramming induces DNA damage, which can have lasting consequences on the quality of the resulting cells. Our studies have shown that DNA damage during reprogramming is induced by abnormalities in DNA replication. However, the cause of DNA damage, the mechanisms of repair, and the developmental consequences of the damage are not well understood. The strength of this proposal is that with the experimental systems used, we are able to identify the specific type of damage induced by reprogramming, and the molecular mechanisms required for repair: we are able to distinguish the role of double strand break HR from the role of stalled replication fork stability. We are also able to distinguish the effect of genome instability on reprogramming efficiency from incomplete transcriptional transitions. We are able to map the sites in the genome with reprogramming-induced damage, and we are able to identify pathways that can be used to increase genome stability and potentially improve developmental competence of reprogrammed stem cells. These studies will provide a mechanistic understanding how genome instability inhibits the induced transition between different cellular states.

项目总结