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Fumarase affects the deoxyribonucleic acid damage response by protecting the mitochondrial desulfurase Nfs1p from

Joyce Yip1, Suqing Wang1, Jasper Tan1

  • 1Department of Microbiology and Immunology, Cancer Programme at NUSMED, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Block MD4, Level 5, Singapore 117545, Singapore.

Iscience
|November 22, 2021
PubMed

Insights

Fumarase protects the Nfs1p enzyme in mitochondria, crucial for DNA repair. Overexpressing Nfs1p compensates for fumarase deficiency, restoring deoxyribonucleic acid (DNA) damage response.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Fumarase, a Krebs cycle enzyme, functions as a tumor suppressor.
  • Fumarase plays a role in the deoxyribonucleic acid (DNA) damage response (DDR) across species.
  • Nfs1p, a cysteine desulfurase, is essential for DNA repair enzyme function.

Purpose of the Study:

  • To investigate the role of fumarase in the DNA damage response.
  • To elucidate the mechanism by which fumarase influences DNA repair.
  • To determine if Nfs1p can compensate for fumarase deficiency in DNA repair.

Main Methods:

  • Utilized yeast cells deficient in fumarase.
  • Studied the effects of Nfs1p overexpression on DNA repair.
  • Analyzed post-translational modifications of Nfs1p under DNA damage conditions.
  • Investigated the interaction between fumarase and Nfs1p in mitochondria.

Main Results:

  • Overexpression of Nfs1p restored DNA repair in fumarase-deficient yeast cells.
  • Yeast cells lacking fumarase showed increased inactivating modifications of Nfs1p during DNA damage.
  • Fumarase directly binds to Nfs1p in mitochondria, maintaining a non-oxidizing environment.
  • This interaction protects Nfs1p from modification and inactivation.

Conclusions:

  • Fumarase protects mitochondrial Nfs1p from post-translational modification, thereby supporting the DNA damage response.
  • Nfs1p is critical for generating iron-sulfur clusters, essential cofactors for DNA repair enzymes.
  • Enhanced Nfs1p activity can overcome fumarase deficiency by boosting DNA repair enzyme function.
Keywords:
BiochemistryBiological sciencesMolecular biology

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