Essential functions of iron-requiring proteins in DNA replication, repair and cell cycle control

Abstract

Eukaryotic cells contain numerous iron-requiring proteins such as iron-sulfur (Fe-S) cluster proteins, hemoproteins and ribonucleotide reductases (RNRs). These proteins utilize iron as a cofactor and perform key roles in DNA replication, DNA repair, metabolic catalysis, iron regulation and cell cycle progression. Disruption of iron homeostasis always impairs the functions of these iron-requiring proteins and is genetically associated with diseases characterized by DNA repair defects in mammals. Organisms have evolved multi-layered mechanisms to regulate iron balance to ensure genome stability and cell development. This review briefly provides current perspectives on iron homeostasis in yeast and mammals, and mainly summarizes the most recent understandings on iron-requiring protein functions involved in DNA stability maintenance and cell cycle control.

Figure 1

Iron uptake and utilization inside the cell. Yeast cells obtain iron through low-affinity (Fe-repleted condition, Fet4p) and high-affinity systems (low Fe condition, Fet3p/Ftr1p and Arn1-4 proteins). Both Fet4p and Fet3p/Ftr1p can only transport Fe²⁺, and these processes require the prior reduction of Fe³⁺ to Fe²⁺ by surface reductases (Fre1 to Fre7) (Herbik et al., ; Holmes-Hampton et al., ; Wu et al., ; Yun et al., 2001). The cytosolic “labile iron pool” is utilized by Fe-S proteins, hemoproteins, ribonucleotide reductases (RNRs), and other iron-requiring proteins that localize in different cellular compartments

Figure 2

Iron uptake, intracellular trafficking and regulation in S. cerevisiae. Iron uptake is performed at the plasma membrane by iron transporters. When iron enters into cytosol, it exists in Fe-S clusters in “labile iron pool” (Muhlenhoff et al., 2010), which is subsequently donated to cytosolic iron-dependent apoproteins through monothiol Grx3p/4p to form holoproteins. Meanwhile, the mitochondrial iron transporters Mrs3p/4p and the vacuolar iron transporter Smf3p, Ccc1p and Fet5p/Fth1p can also accept iron from Grx3p/4p. Grx3p/4p can interact with Fra2p and Aft1p/Aft2p, and the Grx3p/4p- bound Fe-S clusters may function as sensors for the cytosolic iron pool (Lill and Mühlenhoff, ; Muhlenhoff et al., 2010). In low-Fe condition, Aft1p can shuttle between the cytosol and the nucleus in an iron-responsive manner, and functions as a transcriptional activator of iron regulon genes, which subsequently activate high-affinity iron uptake systems (Berthelet et al., ; Lill et al., 2012)