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Impact of DNA repair deficits on sur...

Chechlacz, Magdalena.

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Impact of DNA repair deficits on survival and apoptotic signaling in cerebrocortical neurons.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Impact of DNA repair deficits on survival and apoptotic signaling in cerebrocortical neurons./
作者:	Chechlacz, Magdalena.
面頁冊數:	194 p.
附註:	Adviser: Janice R. Naegele.
Contained By:	Dissertation Abstracts International63-03B.
標題:	Biology, Animal Physiology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3045762
ISBN:	0493597239

Impact of DNA repair deficits on survival and apoptotic signaling in cerebrocortical neurons.
Chechlacz, Magdalena.

Impact of DNA repair deficits on survival and apoptotic signaling in cerebrocortical neurons. - 194 p.

Adviser: Janice R. Naegele.

Thesis (Ph.D.)--Wesleyan University, 2002.

During embryonic neurogenesis many immature cortical cells are eliminated by apoptosis. One explanation is that cells are simply produced in excess and therefore only a few are allowed to survive. Another explanation is that apoptosis eliminates cells with DNA damage and prevents incorporation of defective neurons into functional networks. A third possibility is that apoptosis is a form of cellular selection to generate functional diversity. I have investigated whether apoptosis eliminates defective cells, due to DNA damage that arises during neurogenesis. My research addresses the specific hypothesis that defective DNA repair results in gradual accumulation of DNA strand breaks in neurons and subsequently endangers them to injury. This hypothesis has been tested in primary neuronal cultures derived from mice deficient in one DNA repair enzyme called DNA-dependent protein kinase. This trimeric protein consists of a DNA binding subunit Ku70/80 and the catalytic subunit DNA-PKcs. Previously, our group has reported that DNA-PKcs deficits result in increased apoptosis in the embryonic brain. My <italic>in vitro</italic> studies demonstrate that DNA-PKcs deficiency does not alter neuronal maturation, neurite outgrowth or long-term survival but does increase the risk of apoptosis in response to injury. I show that DNA-PKcs deficient neurons exhibit high levels of DNA breaks but appear normal based on nuclear and neurite morphology. This observation suggests that unrepaired DNA damage accumulates for some time before triggering apoptosis. Therefore, I have tested a second hypothesis that death of DNA-PKcs deficient neurons occurs after high levels of DNA strand breaks provide a signal for the activation of the tumor suppressor protein, p53. To evaluate the role of p53 in apoptosis of DNA-PKcs deficient neurons I inhibited p53 with a pharmacological agent called pifithrin-α. I demonstrated that inhibiting p53 rescues DNA-PKcs deficient neurons from apoptosis. I also show that apoptosis in DNA-PKcs deficient postnatal neurons does not require caspase-mediated pathways. Nevertheless, I found that DNA damage induced apoptosis of cortical neurons is achieved through a loss of mitochondrial membrane potential. My findings support the hypothesis that apoptosis of DNA-PKcs deficient cortical neurons is triggered by accumulation of DNA strand breaks that signal via p53 and mitochondrial permeability changes.

ISBN: 0493597239Subjects--Topical Terms:

1017835
Biology, Animal Physiology.

Impact of DNA repair deficits on survival and apoptotic signaling in cerebrocortical neurons.
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