Excision of mutagenic replication-blocking lesions suppresses cancer but promotes cytotoxicity and lethality in nitrosamine-exposed mice
Name
1-s2.0-S2211124721001789-main.pdf
Description
Published version
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2.46 MB
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Unknown
Checksum (MD5)
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Author(s)
Kay, Jennifer E
Corrigan, Joshua J
Armijo, Amanda L
Nazari, Ilana S
Kohale, Ishwar N
Torous, Dorothea K
Avlasevich, Svetlana L
Croy, Robert G
Wadduwage, Dushan N
Carrasco, Sebastian E
Date Issued
March 2021
Journal
Cell Reports
Publisher
Elsevier BV
Version
Final published version
Abstract
N-Nitrosodimethylamine (NDMA) is a DNA-methylating agent that has been discovered to contaminate water, food, and drugs. The alkyladenine DNA glycosylase (AAG) removes methylated bases to initiate the base excision repair (BER) pathway. To understand how gene-environment interactions impact disease susceptibility, we study Aag-knockout (Aag-/-) and Aag-overexpressing mice that harbor increased levels of either replication-blocking lesions (3-methyladenine [3MeA]) or strand breaks (BER intermediates), respectively. Remarkably, the disease outcome switches from cancer to lethality simply by changing AAG levels. To understand the underlying basis for this observation, we integrate a suite of molecular, cellular, and physiological analyses. We find that unrepaired 3MeA is somewhat toxic, but highly mutagenic (promoting cancer), whereas excess strand breaks are poorly mutagenic and highly toxic (suppressing cancer and promoting lethality). We demonstrate that the levels of a single DNA repair protein tip the balance between blocks and breaks and thus dictate the disease consequences of DNA damage.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Center for Environmental Health Sciences
Massachusetts Institute of Technology. Division of Comparative Medicine
Koch Institute for Integrative Cancer Research at MIT
Center for Precision Cancer Medicine
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/J.CELREP.2021.108864
