Mechanistic and biological considerations of oxidatively damaged DNA for helicase-dependent pathways of nucleic acid metabolism

Abstract

Cells are under constant assault from reactive oxygen species that occur endogenously or arise from environmental agents. An important consequence of such stress is the generation of oxidatively damaged DNA, which is represented by a wide range of non-helix distorting and helix-distorting bulkier lesions that potentially affect a number of pathways including replication and transcription; consequently DNA damage tolerance and repair pathways are elicited to help cells cope with the lesions. The cellular consequences and metabolism of oxidatively damaged DNA can be quite complex with a number of DNA metabolic proteins and pathways involved. Many of the responses to oxidative stress involve a specialized class of enzymes known as helicases, the topic of this review. Helicases are molecular motors that convert the energy of nucleoside triphosphate hydrolysis to unwinding of structured polynucleic acids. Helicases by their very nature play fundamentally important roles in DNA metabolism and are implicated in processes that suppress chromosomal instability, genetic disease, cancer, and aging. We will discuss the roles of helicases in response to nuclear and mitochondrial oxidative stress and how this important class of enzymes help cells cope with oxidatively generated DNA damage through their functions in the replication stress response, DNA repair, and transcriptional regulation.

Keywords: DNA metabolism; DNA repair; Helicase; Human disease; Nucleic acid; Oxidatively damaged DNA; Reactive oxygen species; Replication.

Fig. 1

Disruption of charge transport through the DNA double helix by alternative DNA structure or an oxidized base may signal redox-active Fe-S DNA repair proteins including helicases to sites of DNA damage. See text for details.

Fig. 2

Guanine-rich DNA sequences in the mitochondrial genome and promoters, ribosomal DNA, telomeric repeats, or other regions of the nuclear genome may be targeted by DNA helicases for unwinding to facilitate DNA transactions such as replication, DNA repair, or transcription. See text for details.

Fig. 3

Oxidative stress may have reciprocal effects on epigenetic regulation, mitochondrial function, inflammation, and DNA damage that lead to progressive bone marrow failure prevalent in the genetic disorder Fanconi Anemia. See text for details.