Mol. Cell 69, 113–125 (2018)

The cytosolic iron–sulfur assembly (CIA) pathway adds an iron–sulfur (Fe-S) cluster to client proteins. One member of the CIA, MMS19, is involved in the transfer of a Fe-S cluster to DNA damage repair enzymes such as XPD. Although the CIA has been characterized for some time, the mechanisms for regulating CIA activity were not known. Using proteomic approaches, Weon et al. found that MMS19 interacted with a complex composed of the E3 RING ubiquitin ligase NSE1 and its binding partner, MAGE-F1. NSE1 and MAGE-F1 promoted the ubiquitination and degradation of MMS19 by acting on a C-terminal cluster of five lysine residues. MAGE-F1- and NSE1-mediated degradation of MMS19 resulted in impaired ion homeostasis and reduced incorporation of the Fe-S cluster into MMS19 client proteins, leading to a decrease in their overall stability and their ability to efficiently repair DNA damage. Consistent with this, cells expressing high levels of MAGE-F1 exhibited decreased homologous recombination and were highly sensitive to DNA-damaging agents. Finally, genomic analysis revealed that several cancer types exhibited high amplification of MAGE-F1 and were associated with increased genome instability. The findings from Weon et al. reveal a previously unknown connection between ubiquitination and Fe-S clusters with cancer, and future studies could illuminate the exact cellular conditions or upstream components that stimulate MAGE-F1 and NSE1 activity.