Cytosolic Iron-Sulfur Assembly Is Evolutionarily Tuned by a Cancer-Amplified Ubiquitin Ligase

Mol Cell. 2018 Jan 4;69(1):113-125.e6. doi: 10.1016/j.molcel.2017.11.010. Epub 2017 Dec 7.

Abstract

The cytosolic iron-sulfur (Fe-S) cluster assembly (CIA) pathway functions to incorporate inorganic Fe-S cofactors into a variety of proteins, including several DNA repair enzymes. However, the mechanisms regulating the CIA pathway are unknown. We describe here that the MAGE-F1-NSE1 E3 ubiquitin ligase regulates the CIA pathway through ubiquitination and degradation of the CIA-targeting protein MMS19. Overexpression or knockout of MAGE-F1 altered Fe-S incorporation into MMS19-dependent DNA repair enzymes, DNA repair capacity, sensitivity to DNA-damaging agents, and iron homeostasis. Intriguingly, MAGE-F1 has undergone adaptive pseudogenization in select mammalian lineages. In contrast, MAGE-F1 is highly amplified in multiple human cancer types and amplified tumors have increased mutational burden. Thus, flux through the CIA pathway can be regulated by degradation of the substrate-specifying MMS19 protein and its downregulation is a common feature in cancer and is evolutionarily controlled.

Keywords: DNA repair; MAGE; MMS19; NSE1; cancer; iron sulfur; ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CRISPR-Cas Systems
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • DNA Damage / genetics
  • DNA Repair / genetics*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Iron / chemistry*
  • Iron-Sulfur Proteins / metabolism
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Sulfur / chemistry*
  • Transcription Factors / metabolism*
  • Ubiquitination

Substances

  • Carrier Proteins
  • Iron-Sulfur Proteins
  • MMS19 protein, human
  • Microtubule-Associated Proteins
  • NSMCE1 protein, human
  • Neoplasm Proteins
  • Transcription Factors
  • cytoplasmic linker protein 170
  • Sulfur
  • Iron