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（由申请人提供）：多倍体细胞含有两组以上完整的同源染色体，包括心脏、肝脏和胎盘在内的多个重要器官都含有多倍体细胞。尽管多倍体很普遍，但其生物学意义仍不清楚，即多倍体细胞中额外的染色体组可以缓冲基因组损伤剂的影响，从而使得多倍体细胞对 DNA 损伤的耐受性更强。当受到 DNA 损伤时，二倍体细胞会激活典型反应，以防止 DNA 损伤的细胞进入细胞周期。如果没有这种反应，细胞就会带着受损的 DNA 进入有丝分裂，并经常通过死亡。与二倍体细胞相比，我们对多倍体细胞如何响应 DNA 损伤知之甚少。我们的实验室发现，与许多多倍体细胞不同，果蝇直肠乳头细胞（以下简称：乳头细胞）进行有丝分裂增殖，因此，与二倍体细胞相比，果蝇乳头细胞使我能够研究 DNA 损伤对自然有丝分裂的多倍体细胞的影响。发现乳头细胞的染色体不稳定率升高，这表明它们缺乏典型的 DNA 损伤反应。我发现不同类型的 DNA 损伤会引起不同的、具体来说，乳头细胞对 X 射线照射引起的 DNA 损伤具有高度耐受性，但会死亡。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，我将确定多倍体乳头细胞的非典型机制。在目标 2 中，我期望揭示失去典型 DNA 损伤反应的细胞能够在高水平的辐射诱导的 DNA 损伤中生存的基本机制。我将确定多倍体乳头细胞响应再复制诱导的 DNA 损伤而发生细胞死亡的非典型机制，这项研究应该揭示人们对 MC 知之甚少的机制，这是一种对于缺乏典型细胞的细胞死亡机制至关重要的机制。总而言之，我提出的研究将确定多倍体乳头细胞对 DNA 损伤作出反应的具体机制。我发现多倍体细胞和多倍体细胞之间的一个主要区别尚未得到研究。二倍体细胞是它们对 DNA 损伤的反应，由于缺乏典型的 DNA 损伤反应和多倍体是许多癌症中反复出现的特征，因此了解多倍体细胞对 DNA 损伤反应的不同方式对于治疗多倍体癌症至关重要。