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Evaluation of the Role of Human DNA ...

Herman, Kimberly N.

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Evaluation of the Role of Human DNA polymerase eta on Mutagenesis in a Cell-Based Model.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Evaluation of the Role of Human DNA polymerase eta on Mutagenesis in a Cell-Based Model./
作者:	Herman, Kimberly N.
面頁冊數:	167 p.
附註:	Source: Dissertation Abstracts International, Volume: 76-11(E), Section: B.
Contained By:	Dissertation Abstracts International76-11B(E).
標題:	Biochemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3710621
ISBN:	9781321866032

Evaluation of the Role of Human DNA polymerase eta on Mutagenesis in a Cell-Based Model.
Herman, Kimberly N.

Evaluation of the Role of Human DNA polymerase eta on Mutagenesis in a Cell-Based Model. - 167 p.

Source: Dissertation Abstracts International, Volume: 76-11(E), Section: B.

Thesis (Ph.D.)--North Carolina State University, 2015.

DNA damage occurs constantly throughout the cell cycle, and can occur intrinsically from DNA synthesis errors and as a side effect of oxidative respiration or extrinsically from DNA damaging agents such as chemical and dietary exposures or exposure to ultraviolet light (UV) from the sun. The main DNA damage caused by UV is cyclobutane pyrimidine dimers (CPDs). Additionally, DNA can be damaged by chemical exposure. An example is the use of mustard gas in military applications, which were later modified and utilized as chemotherapeutic agents. Two chemicals that we are studying include one of these modified mustard gases, cis-diamminedichloroplatinum (cisplatin), as well as another chemical called N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). These treatments can cause lesions which block the replication fork and have to be bypassed by a special tolerance mechanism called translesion synthesis (TLS). TLS is performed by special polymerases which have wide open active sites to accommodate bulky lesions. These open active sites are great for accommodating lesions, but also do not have the tight fit of replicative polymerases which can lead to errors and mutagenesis.

ISBN: 9781321866032Subjects--Topical Terms:

518028
Biochemistry.

Evaluation of the Role of Human DNA polymerase eta on Mutagenesis in a Cell-Based Model.
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245 1 0 $a Evaluation of the Role of Human DNA polymerase eta on Mutagenesis in a Cell-Based Model.
300 $a 167 p.
500 $a Source: Dissertation Abstracts International, Volume: 76-11(E), Section: B.
500 $a Adviser: Scott D. McCulloch.
502 $a Thesis (Ph.D.)--North Carolina State University, 2015.
520 $a DNA damage occurs constantly throughout the cell cycle, and can occur intrinsically from DNA synthesis errors and as a side effect of oxidative respiration or extrinsically from DNA damaging agents such as chemical and dietary exposures or exposure to ultraviolet light (UV) from the sun. The main DNA damage caused by UV is cyclobutane pyrimidine dimers (CPDs). Additionally, DNA can be damaged by chemical exposure. An example is the use of mustard gas in military applications, which were later modified and utilized as chemotherapeutic agents. Two chemicals that we are studying include one of these modified mustard gases, cis-diamminedichloroplatinum (cisplatin), as well as another chemical called N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). These treatments can cause lesions which block the replication fork and have to be bypassed by a special tolerance mechanism called translesion synthesis (TLS). TLS is performed by special polymerases which have wide open active sites to accommodate bulky lesions. These open active sites are great for accommodating lesions, but also do not have the tight fit of replicative polymerases which can lead to errors and mutagenesis.
520 $a We first an environmentally relevant UV-B treatment in a normal human fibroblast control line and a Xeroderma pigmentosum variant (XP-V) cell line, in which the POLH gene contains a truncating point mutation leading to a non-functional polymerase. We demonstrate that UV-B has similar but less striking effects compared to UV-C in both its cytotoxic and mutagenic effects. Analysis of the mutation spectra after a single dose of UV-B shows a majority of mutations can be attributed to mutagenic bypass of dipyrimidine sequences. However, we do note additional types of mutations with UV-B that are not previously reported after UV-C exposure.
520 $a Reactive oxygen species (ROS) can also cause DNA damage. One of the main damaging oxidative lesions is 7,8-dihydro-8-oxoguanine (8-oxoG). This lesion can inhibit the replication fork and has been linked to mutagenesis, cancer and aging. In vitro studies have shown that the translesion synthesis polymerase, DNA polymerase eta (pol eta), is able to efficiently bypass 8-oxoG in DNA. In this study we wanted to investigate the mutagenic effects of oxidative stress, and in particular 8-oxoG, in the presence and absence of pol eta. We quantified levels of oxidative stress, 8-oxoG levels in DNA, and nuclear mutation rates. We found that most of the 8-oxoG detected were localized to the mitochondrial DNA, opposed to the nuclear DNA. We also saw a corresponding lack of mutations in a nuclear encoded gene. This suggests that oxidative stress' primary mutagenic effects are not predominantly on genomic DNA.
520 $a Next we evaluated the response to DNA damage by evaluating the effects of DNA damaging agents on TLS polymerase mRNA levels over time. We used UV-B treatment, cisplatin, and MNNG on two cell lines with either, proficient, or deficient pol eta. We measured mRNA levels by qPCR at 1, 4, 8 16 and 24 hours post treatment. We found an overall suppression of mRNA levels across most treatments and polymerases at 1 hour post treatment. A delayed increase in pol eta expression was observed when a low dose of UV-B was used in the pol eta proficient cells, and in the pol eta deficient cells we saw a subsequent rise in likely back-up polymerases including pol tau. When using a high dose of UV-B we observed a prolonged suppression of mRNA levels of TLS polymerase genes. Our results for MNNG were similar to previously reported MNNG, and cisplatin results showed that the pol eta message increased in normal cells and that there was a rise in back-up polymerases message levels including pol tau in pol eta deficient cells.
590 $a School code: 0155.
650 4 $a Biochemistry. $3 518028
650 4 $a Biology. $3 522710
650 4 $a Cellular biology. $3 3172791
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710 2 $a North Carolina State University. $3 1018772
773 0 $t Dissertation Abstracts International $g 76-11B(E).
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793 $a English
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