DNA Replication in Animal Systems Lacking Thioredoxin Reductase I

Abstract

Ribonucleotide reductase (RNR) activity is generally required to provide deoxyribonucleoside triphosphates (dNTPs or DNA-precursors) for DNA replication (Thelander and Reichard, 1979). This property has made both RNR and the pathways RNR depends upon important drug-targets. For example, the drug hydroxyurea is a specific inhibitor of RNR and has been used for many decades as an effective chemotherapeutic agent for certain cancers and viral diseases (Navarra and Preziosi, 1999; Wright et al., 1990; Yarbro, 1992). This chapter focuses on two critical pathways that lie upstream of RNR and are important for supporting RNR activity: namely, the glutathione (GSH) pathway and the thioredoxin (Trx) pathway. These pathways were first uncovered in bacterial systems roughly fifty years ago. In the ensuing half-century, the components and activities of these pathways have been intensely studied in bacterial, archaebacterial, and eukaryotic systems, both in vivo and in vitro (Holmgren, 1977; Holmgren, 1989). The GSH and Trx pathways, themselves, are ubiquitous in biology, yet various components of the pathways exhibit activities and, in some cases, evolutionary histories, that are particular to animal systems. Classic descriptive and biochemical studies laid the groundwork for understanding these pathways in animals; however, only in recent years have genetic systems been established in which the physiological activities of these pathways could be tested (Arner, 2009; Holmgren and Lu, 2010; Holmgren and Sengupta, 2010). Here I will overview the Trx and GSH pathways and their contributions to DNA replication. Particular attention will be paid to recent revelations on the activities and properties of these systems in animals that differ from those in other biological systems. Some recent advances have come from the development of mouse models bearing targeted “conditional” alleles of the gene encoding thioredoxin reductase I (TrxR1, also called Txnrd1 or TR1), which can be disrupted in a cell typeor developmental stage-specific manner. Whereas these models are yielding some exciting insights into the Trx and GSH systems in embryonic development, stress responses, toxicology, cancer, and other processes (Bondareva et al., 2007; Branco et al., 2011; Carvalho et al., 2008; Jakupoglu et al., 2005; Mandal et al., 2010; Rogers et al., 2004; Suvorova et al., 2009; Tipple et al., 2007; Zhang and Lu, 2007), the current treatise will emphasize the interplay of these pathways in supporting DNA replication in animal systems. The enormity of the body of literature on the Trx, GSH, and RNR systems precludes an exhaustive review of these materials, and it is my intention to cover these subjects in only a cursory manner to set the backdrop for understanding these systems in the context of DNA replication in animals. The reader is directed to more