Non-Canonical Responses to DNA damage in Drosophila Polyploid Cells

果蝇多倍体细胞对 DNA 损伤的非典型反应

基本信息

批准号：
9014417
负责人：
Heidi Bretscher
金额：
$ 3.4万
依托单位：
DUKE UNIVERSITY
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：
2015-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9014417
关键词：
ATM function Address Apoptosis Biological Biological Process Buffers Cancerous Caspase Cell Cycle Cell Death Cell Death Process Cells Centrosome Cessation of life Chromosomal Instability Chromosomes DNA DNA Damage DNA Fragmentation DNA Repair DNA Sequence Alteration DNA biosynthesis Developmental Process Diploid Cells Drosophila genus Exhibits G22P1 gene Genome Genomic Instability Genotoxic Stress Goals Heart In complete remission Light Liver Malignant Neoplasms Mitosis Mitotic Mitotic Cell Cycle Modeling Mus Organ Pathologic Processes Pathway interactions Placenta Polyploid Cells Polyploidy Prevalence Process Radiation Induced DNA Damage Research Single-Stranded DNA Source System TP53 gene Therapeutic Therapeutic Intervention Tissues Work ataxia telangiectasia mutated protein cancer cell cell type daughter cell fly genome integrity in vivo irradiation prevent programs public health relevance rectal repaired response segregation sensor tumor whole genome

项目摘要

DESCRIPTION (provided by applicant): Polyploid cells contain more than two complete sets of homologous chromosomes. Polyploid cells occur both naturally and pathologically. Several vital organs, including the heart, liver and placenta contain polyploid cells. Further, many cancers exist in a polyploid or near polyploid state. Despite the prevalence of polyploidy, its biological implications remain unclear. One model is that extra sets of chromosomes in polyploid cells buffer the effects of genome damaging agents, thus making polyploid cells more tolerant of DNA damage. When subjected to DNA damage, diploid cells activate a canonical response to prevent cells with DNA damage from entering the cell cycle. In the absence of this response, cells enter mitosis with damaged DNA and frequently die via a poorly characterized cell death process known as mitotic catastrophe (MC). In contrast to diploid cells, little is known about how a polyploid cell responds to DNA damage. My objective is to examine how polyploid cells respond to DNA damage. Previously, our lab found that unlike many polyploid cells, Drosophila rectal papillar (hereafter: papillar cells) cells undergo mitotic proliferation. Thus, Drosophila papillar cells allow me to investigate the effects of DNA damage on naturally occurring mitotic polyploid cells. Compared to diploid cells, our lab has found that papillar cells show elevated rates of chromosomal instability, suggesting that they lack a canonical DNA damage response. I have found that distinct types of DNA damage elicit distinct, non-canonical responses in papillar cells. Specifically, papillar cells are highly tolerant of X-irradiation induced DNA damage but die via non-canonical (caspase-independent) MC following aberrant DNA replication. Therefore, my central hypothesis is that polyploid mitotic cells employ non-canonical mechanisms following DNA damage. In Aim 1 I will determine the non-canonical mechanism by which polyploid papillar cells survive irradiation induced DNA damage. I expect to uncover the basic mechanism by which cells stripped of canonical DNA damage responses can survive high levels of irradiation induced DNA damage. In Aim 2 I will determine the non-canonical mechanism by which polyploid papillar cells undergo cell death in response to re-replication induced DNA damage. This research should shed light on the poorly understood mechanisms of MC, a cell death mechanism that is crucial in cells lacking canonical DNA damage responses. Taken together, my proposed research will identify specific mechanisms by which polyploid papillar cells respond to DNA damage. The biological implications of polyploidy remain largely unstudied. I have found that one main difference between polyploid cells and diploid cells is their response to DNA damage. Since both lack of canonical DNA damage responses and polyploidy are recurring features in numerous cancers, understanding distinct ways by which polyploid cells respond to DNA damage is crucial in treatment of polyploid cancers.

描述（由适用提供）：多倍体细胞包含两组以上的同源染色体。多倍体细胞在自然和病理上出现。几个重要器官，包括心脏，肝脏和斑点包含多倍体细胞。此外，许多癌症存在于多倍体或多倍体状态。尽管多倍体的流行率，但其生物学意义仍然不清楚。一种模型是，多倍体细胞中的额外染色体集缓冲基因组损伤剂的作用，从而使多倍体细胞对DNA损伤的耐受性更高。当受到DNA损伤时，二倍体细胞会激活一个规范反应，以防止DNA损伤进入细胞周期的细胞。在没有这种反应的情况下，细胞因DNA受损而进入有丝分裂，并且经常通过被称为有丝分裂灾难（MC）的细胞死亡过程而死亡。与二倍体细胞相反，多倍体细胞对DNA损伤的反应知之甚少。我的目标是检查多倍体细胞如何应对DNA损伤。以前，我们的实验室发现，与许多多倍体细胞不同，果蝇直肠乳头（以下简称：乳头状细胞）细胞会经历有丝分裂增殖。果蝇乳头细胞使我能够研究DNA损伤对天然存在的有丝分裂多倍体细胞的影响。与二倍体细胞相比，我们的实验室发现，乳头状细胞显示出染色体不稳定性率升高，这表明它们缺乏规范的DNA损伤响应。我发现，不同类型的DNA损伤引起了乳头细胞中不同的非传统反应。具体而言，乳头细胞高度耐受X辐射诱导的DNA损伤，但死亡通过异常DNA复制后，通过非典型的（caspase无关）MC。因此，我的中心假设是多倍体有丝分裂细胞在DNA损伤后采用非典型机制。在AIM 1中，我将确定多倍体乳头细胞在辐射引起的DNA损伤的非规范机制中。我期望揭示剥离大量DNA损伤反应的细胞可以生存高水平的辐照引起的DNA损伤的基本机制。在AIM 2中，我将确定多倍体乳头状细胞在重新复制引起的DNA损伤的反应中，通过这些机制，通过这些机制。这项研究应阐明MC的理解较低的机制，MC的机制是一种细胞死亡机制，对于缺乏规范DNA损伤反应的细胞至关重要。综上所述，我提出的研究将确定多倍体乳头细胞对DNA损伤反应的特定机制。多倍体的生物学意义在很大程度上仍然没有研究。我发现多倍体细胞和二倍体细胞之间的一个主要区别是它们对DNA损伤的反应。由于缺乏规范的DNA损伤反应和多倍体均具有许多癌症的重复特征，因此了解多倍体细胞对DNA损伤的不同方式对于治疗多倍体癌症至关重要。