**8. References**

82 DNA Repair

Fig. 4. Circos diagram showing the top 15 DNA motifs found in promoters of checkpoint factor genes and their related transcription factors (number of occurrences are multiplied by

This chapter provides a summary of research into transcriptional regulatory networks controlling DNA repair pathways, bidirectional versus unidirectional promoters of DNA repair genes, and bidirectional promoters of breast and ovarian cancer genes. DNA words are shared among these promoters, and these words represent both known and unknown binding sites for transcription factors. When possible, we report the highest scoring assignment of transcription factor to DNA word. Our research represents a novel approach to identifying factors involved in transcriptional regulation of DNA repair genes. Many of these proteins have dual roles in transcription and DNA repair. Although many of the regulatory relationships are characterized at the level of protein-protein interactions, little research is available on the transcriptional regulatory networks that control DNA repair gene expression. We present evidence that regulatory networks exist among these genes, and support the claim that bidirectional promoters (implicated in B/O cancers) have a distinct network from unidirectional promoters. The identification of putative binding sites provides the first step in the elucidation of higher-order interdependencies among DNA repair genes in the cell. We also report preliminary findings on pairs of binding sites that represent regulatory modules. Furthermore, we show that there is much overlap among promoters of DNA repair genes, and that shared DNA binding motifs can be distributed among a collection of alternative promoters, each having distinct combinations of regulatory elements. The complex nature of the data can be simplified for visual interpretation using

visualization techniques such as network modeling and circos diagrams.

100).

**6. Conclusions** 


**6** 

**Mitochondrial DNA Damage:** 

**Role of Ogg1 and Aconitase** 

*1Clinical Medicine Research Center, Affiliated Hospital of Guangdong Medical College 2Department of Medicine, Northwestern University Feinberg School of Medicine and Jesse* 

Mitochondria have a vital role in respiration-coupled energy production, amino acid and fatty acid metabolism, Fe2+/Ca2+ homeostasis and the integration of apoptotic signals that regulate cellular life and death (Babcock et al., 1997; Loeb et al., 2005; Taylor & Turnbull, 2005; Kroemer et al., 2007). Given the importance of these cellular functions regulated by the mitochondria with implications for aging, degenerative diseases and carcinogenesis, it is not surprising that this organelle has been the subject of intensive investigation for decades and continues to challenge investigators. Mitochondria produce nearly 90% of all the energy made in the body by oxidative phosphorylation that occurs via the electron transport chain (ETC). Mitochondria are the major cellular site of reactive oxygen species (ROS) production. It is estimated that 1–5% of the oxygen consumed in the mitochondrial ETC is converted to ROS (Kroemer et al., 2007). Mammalian mitochondria have a covalently closed round mitochondrial DNA (mtDNA) that is replicated and expressed within the mitochondria in close proximity to the ETC and potentially damaging ROS (Clayton 1982; Clayton 1984; Kroemer et al., 2007). Mammalian mtDNA contains 37 genes that encode 13 proteins (all of which are involved in the ETC), 22 tRNAs, and 2 rRNAs (Anderson et al., 1981). The remaining mitochondrial ETC proteins, the metabolic enzymes, the DNA and RNA

polymerases and the ribosomal proteins are all encoded by nuclear genome.

Oxidative stress-induced mtDNA damage is implicated in a wide range of pathologic processes including carcinogenesis, aging and degenerative diseases of various organs and tissues (Bohr et al., 2002; Van Houten et al., 2006; Kroemer et al., 2007; Gredilla et al., 2010). In this review, we summarize the evidence that mtDNA damage augments mitochondriaregulated (intrinsic) apoptosis; an event that underlies the pathophysiologic mechanisms of diverse diseases. We focus our attention on one form of oxidative stress, exposure to asbestos fibers, which are well known to cause pulmonary fibrosis (asbestosis) and malignancies (e.g. mesothelioma and lung cancer). Specifically, we examine the role of a mitochondrial oxidative DNA repair enzyme (8-oxoguanine DNA glycosylase; Ogg1) and a recently described novel mechanism whereby mitochondrial Ogg1 acts as a mitochondrial aconitase chaperone protein to prevent oxidant-induced alveolar epithelial cell (AEC) mitochondrial dysfunction and intrinsic apoptosis. We discuss studies showing that

**1. Introduction** 

Gang Liu1 and David W. Kamp2

*Brown VA Medical Center* 

*1PR China 2USA* 

