Excessive Reactive Oxygen Species and Exotic DNA Lesions as an Exploitable Liability.

Abstract:

:Although the terms "excessive reactive oxygen species (ROS)" and "oxidative stress" are widely used, the implications of oxidative stress are often misunderstood. ROS are not a single species but a variety of compounds, each with unique biochemical properties and abilities to react with biomolecules. ROS cause activation of growth signals through thiol oxidation and may lead to DNA damage at elevated levels. In this review, we first discuss a conceptual framework for the interplay of ROS and antioxidants. This review then describes ROS signaling using FLT3-mediated growth signaling as an example. We then focus on ROS-mediated DNA damage. High concentrations of ROS result in various DNA lesions, including 8-oxo-7,8-dihydro-guanine, oxazolone, DNA-protein cross-links, and hydantoins, that have unique biological impacts. Here we delve into the biochemistry of nine well-characterized DNA lesions. Within each lesion, the types of repair mechanisms, the mutations induced, and their effects on transcription and replication are discussed. Finally, this review will discuss biochemically inspired implications for cancer therapy. Several teams have put forward designs to harness the excessive ROS and the burdened DNA repair systems of tumor cells for treating cancer. We discuss inhibition of the antioxidant system, the targeting of DNA repair, and ROS-activated prodrugs.

journal_name

Biochemistry

journal_title

Biochemistry

authors

AbdulSalam SF,Thowfeik FS,Merino EJ

doi

10.1021/acs.biochem.6b00703

subject

Has Abstract

pub_date

2016-09-27 00:00:00

pages

5341-52

issue

38

eissn

0006-2960

issn

1520-4995

journal_volume

55

pub_type

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