Understanding cell fate decisions in response to 0⁶-Methylguanine DNA lesions
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2011.
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| Format: | Thesis |
| Language: | eng |
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Massachusetts Institute of Technology
2013
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| Online Access: | http://hdl.handle.net/1721.1/76170 |
| _version_ | 1826214074714685440 |
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| author | Noonan, Ericka Marie |
| author2 | Leona D. Samson and Douglas A. Lauffenburger. |
| author_facet | Leona D. Samson and Douglas A. Lauffenburger. Noonan, Ericka Marie |
| author_sort | Noonan, Ericka Marie |
| collection | MIT |
| description | Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2011. |
| first_indexed | 2024-09-23T15:59:24Z |
| format | Thesis |
| id | mit-1721.1/76170 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T15:59:24Z |
| publishDate | 2013 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/761702019-04-10T13:20:00Z Understanding cell fate decisions in response to 0⁶-Methylguanine DNA lesions Noonan, Ericka Marie Leona D. Samson and Douglas A. Lauffenburger. Massachusetts Institute of Technology. Dept. of Biological Engineering. Massachusetts Institute of Technology. Dept. of Biological Engineering. Biological Engineering. Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2011. Cataloged from PDF version of thesis. Includes bibliographical references. The stability of the genome is constantly challenged by both endogenous and exogenous DNA damaging agents. DNA damage, if left unrepaired, can give rise to permanent genetic alterations that ultimately increase our risk of cancer and other diseases. To combat these threats, eukaryotic cells activate a DNA damage response (DDR) that coordinates a wide variety of cellular processes including cell cycle progression, DNA repair, or in the case of severe/irreparable damage, apoptotic cell death. In addition to its role in cancer prevention, the DDR is fundamental in cancer treatment as noted by the numerous DNA damage-based chemotherapies. Thus, understanding how cell fate is determined by consequences of DDR is important for basic biological science and for medical applications. Alkylating agents comprise a major class of DNA damaging chemotherapeutics. The 0⁶MeG DNA lesion is a highly mutagenic, carcinogenic, and cytotoxic lesion produced by SNl methylating agents. Additionally, persistent 0⁶MeG lesions induce apoptosis in an 0⁶MeG DNA methyltransferase (MGMT) repair- and mismatch repair (MMR)-dependent manner. Here, we examine the DNA damage response induced by the 0⁶MeG lesion at both the molecular and cellular level after treatment with the SN1 methylating agent N-methyl-N'-nitro-Nnitrosoguanidine (MNNG). A systems-level approach combining various experimental techniques was used to quantitatively monitor the temporal regulation of DDR network proteins and, in parallel, phenotypic responses (cell cycle arrest, DNA replication, and apoptosis) induced by 0⁶MeG lesions. Through this approach, we have shown that TK6 human lymphoblastoid cells undergo cell cycle delay through both the first and second cell cycle post treatment. Furthermore, we demonstrate that 0⁶MeG triggers an intra-S-phase arrest in the second S-phase that ultimately leads to cell cycle progression and survival in cells with low/repairable amounts of damage or apoptosis in cells with high/irreparable amounts of damage. Based on the signaling and phenotypic data acquired, we developed a conceptual model for MMR's role in triggering cell cycle arrest and cell death. In addition, exploration of the global transcriptional response provided an unbiased approach to further elucidate previously unrecognized biological processes involved in the response to MNNG-induced damage. Taken together, our results have enhanced our understanding of the cellular response to alkylation-induced damage and will contribute to the development of personalized chemotherapeutic treatments in the future. by Ericka Marie Noonan. Ph.D. 2013-01-07T21:29:57Z 2013-01-07T21:29:57Z 2011 2011 Thesis http://hdl.handle.net/1721.1/76170 820728573 eng MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission. http://dspace.mit.edu/handle/1721.1/7582 323 p. application/pdf Massachusetts Institute of Technology |
| spellingShingle | Biological Engineering. Noonan, Ericka Marie Understanding cell fate decisions in response to 0⁶-Methylguanine DNA lesions |
| title | Understanding cell fate decisions in response to 0⁶-Methylguanine DNA lesions |
| title_full | Understanding cell fate decisions in response to 0⁶-Methylguanine DNA lesions |
| title_fullStr | Understanding cell fate decisions in response to 0⁶-Methylguanine DNA lesions |
| title_full_unstemmed | Understanding cell fate decisions in response to 0⁶-Methylguanine DNA lesions |
| title_short | Understanding cell fate decisions in response to 0⁶-Methylguanine DNA lesions |
| title_sort | understanding cell fate decisions in response to 0⁶ methylguanine dna lesions |
| topic | Biological Engineering. |
| url | http://hdl.handle.net/1721.1/76170 |
| work_keys_str_mv | AT noonanerickamarie understandingcellfatedecisionsinresponseto06methylguaninednalesions |