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Aag DNA glycosylase promotes alkylation-induced tissue damage mediated by Parp1

Jennifer A Calvo1, Catherine A Moroski-Erkul, Annabelle Lake

  • 1Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.

Plos Genetics
|April 18, 2013
PubMed

Insights

Alkyladenine DNA glycosylase (AAG) initiates DNA repair that causes tissue damage and lethality from chemotherapy alkylating agents. Suppressing AAG or Parp1 protects against these chemotherapy side effects.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Alkylating agents are crucial chemotherapy drugs but cause significant side effects by damaging healthy tissues.
  • Base excision repair (BER) is vital for DNA repair, but its initiation can be harmful under specific conditions.

Purpose of the Study:

  • To investigate the role of alkyladenine DNA glycosylase (AAG) in chemotherapy-induced tissue damage and lethality.
  • To determine the relationship between AAG, BER, and Parp1 in mediating the toxic effects of alkylating agents.

Main Methods:

  • Utilized wild-type, Aag transgenic, and Aag knockout mice to assess AAG-dependent tissue damage.
  • Examined various tissues including cerebellum, spleen, thymus, bone marrow, pancreas, and retina.
  • Conducted genetic experiments involving Parp1 modulation to dissect its role in AAG-mediated damage.

Main Results:

  • AAG mediates alkylation-induced tissue damage and lethality across multiple cell types.
  • Aag deficiency completely suppressed chemotherapy-induced tissue damage and lethality.
  • Parp1 is essential for AAG-mediated tissue damage, with cytotoxicity abrogated in Parp1-deficient mice.

Conclusions:

  • AAG-initiated BER plays a critical role in the detrimental side effects of alkylating agent chemotherapies.
  • Parp1 is crucial in mediating AAG-induced tissue damage, highlighting a potential therapeutic target.

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