MIT Libraries logoDSpace@MIT

MIT
View Item 
  • DSpace@MIT Home
  • MIT Open Access Articles
  • MIT Open Access Articles
  • View Item
  • DSpace@MIT Home
  • MIT Open Access Articles
  • MIT Open Access Articles
  • View Item
JavaScript is disabled for your browser. Some features of this site may not work without it.

O[superscript 6]-Methylguanine DNA lesions induce an intra-S-phase arrest from which cells exit into apoptosis governed by early and late multi-pathway signaling network activation

Author(s)
Noonan, Ericka M.; Shah, Dharini; Yaffe, Michael B; Lauffenburger, Douglas A; Samson, Leona D
Thumbnail
DownloadYaffe_o(6)-Methylguanine.pdf (6.315Mb)
OPEN_ACCESS_POLICY

Open Access Policy

Creative Commons Attribution-Noncommercial-Share Alike

Terms of use
Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/
Metadata
Show full item record
Abstract
The O[superscript 6]-methylguanine (O[superscript 6]MeG) DNA lesion is well known for its mutagenic, carcinogenic, and cytotoxic properties, and understanding how a cell processes such damage is of critical importance for improving current cancer therapy. Here we use human cells differing only in their O[superscript 6]MeG DNA methyltransferase (MGMT) or mismatch repair (MMR) status to explore the O[superscript 6]MeG/MMR-dependent molecular and cellular responses to treatment with the methylating agent N-methyl-N′-nitro-N-nitrosoguanidine (MNNG). We find that O[superscript 6]MeG triggers MMR-dependent cell cycle perturbations in both the first and second cell cycle post treatment. At lower levels of damage, we show that a transient arrest in the second S-phase precedes survival and progression into subsequent cell cycles. However, at higher levels of damage, arrest in the second S-phase coincides with a cessation of DNA replication followed by initiation of apoptotic cell death. Further, we show that entry into apoptotic cell death is specifically from S-phase of the second cell cycle. Finally, we demonstrate the key role of an O[superscript 6]MeG/MMR-dependent multi-pathway, multi-time-scale signaling network activation, led by early ATM, H2AX, CHK1, and p53 phosphorylation and followed by greatly amplified late phosphorylation of the early pathway nodes along with activation of the CHK2 kinase and the stress-activated JNK kinase.
Date issued
2012-08
URI
http://hdl.handle.net/1721.1/85197
Department
Massachusetts Institute of Technology. Center for Environmental Health Sciences; Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Biology; Koch Institute for Integrative Cancer Research at MIT
Journal
Integrative Biology
Publisher
Royal Society of Chemistry, The
Citation
Noonan, Ericka M., Dharini Shah, Michael B. Yaffe, Douglas A. Lauffenburger, and Leona D. Samson. “O6-Methylguanine DNA Lesions Induce an Intra-S-Phase Arrest from Which Cells Exit into Apoptosis Governed by Early and Late Multi-Pathway Signaling Network Activation.” Integr. Biol. 4, no. 10 (2012): 1237.
Version: Author's final manuscript
ISSN
1757-9694
1757-9708

Collections
  • MIT Open Access Articles

Browse

All of DSpaceCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects

My Account

Login

Statistics

OA StatisticsStatistics by CountryStatistics by Department
MIT Libraries
PrivacyPermissionsAccessibilityContact us
MIT
Content created by the MIT Libraries, CC BY-NC unless otherwise noted. Notify us about copyright concerns.