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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：
8835647
负责人：
Heidi Bretscher
金额：
$ 3.35万
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/8835647
关键词：
ATM function Address Am 80 Apoptosis Ataxia-Telangiectasia-Mutated protein kinase 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 Research Single-Stranded DNA Source System Therapeutic Therapeutic Intervention Tissues Work cancer cell cell type daughter cell fly genome integrity in vivo irradiation prevent programs public health relevance rectal repaired response segregation sensor tumor

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.