Maintenance of genome integrity by the late-acting cytoplasmic iron-sulfur assembly (CIA) complex

Petronek, Michael; Allen, Bryan G.

doi:10.3389/fgene.2023.1152398

Cited by 10 publications

(2 citation statements)

References 132 publications

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“…A possible explanation for these observations may relate to the impaired function of nuclear iron-sulfur (Fe-S) clusters following iron limitation. Several key DNA metabolic enzymes (including DNA primase and eukaryotic DNA polymerases, DNA repair helicases, nucleases, glycosylases, demethylases, and ribonucleotide reductase) contain a [4Fe-4S] 2+ cluster (or a di-ferric center in the case of ribonucleotide reductase) that must be intact for enzymatic activity and high-fidelity DNA replication [1,44]. Consistent with this hypothesis, impaired Fe-S biogenesis has been shown to cause the degradation of [4Fe-4S] 2+ containing DNA metabolic enzymes, resulting in replication fork collapse, genomic instability, and cell death [45][46][47].…”

Section: Discussionmentioning

confidence: 99%

Depletion of Labile Iron Induces Replication Stress and Enhances Responses to Chemoradiation in Non-Small-Cell Lung Cancer

Bayanbold,

Singhania,

Fath

et al. 2023

Antioxidants

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The intracellular redox-active labile iron pool (LIP) is weakly chelated and available for integration into the iron metalloproteins that are involved in diverse cellular processes, including cancer cell-specific metabolic oxidative stress. Abnormal iron metabolism and elevated LIP levels are linked to the poor survival of lung cancer patients, yet the underlying mechanisms remain unclear. Depletion of the LIP in non-small-cell lung cancer cell lines using the doxycycline-inducible overexpression of the ferritin heavy chain (Ft-H) (H1299 and H292), or treatment with deferoxamine (DFO) (H1299 and A549), inhibited cell growth and decreased clonogenic survival. The Ft-H overexpression-induced inhibition of H1299 and H292 cell growth was also accompanied by a significant delay in transit through the S-phase. In addition, both Ft-H overexpression and DFO in H1299 resulted in increased single- and double-strand DNA breaks, supporting the involvement of replication stress in the response to LIP depletion. The Ft-H and DFO treatment also sensitized H1299 to VE-821, an inhibitor of ataxia telangiectasis and Rad2-related (ATR) kinase, highlighting the potential of LIP depletion, combined with DNA damage response modifiers, to alter lung cancer cell responses. In contrast, only DFO treatment effectively reduced the LIP, clonogenic survival, cell growth, and sensitivity to VE-821 in A549 non-small-cell lung cancer cells. Importantly, the Ft-H and DFO sensitized both H1299 and A549 to chemoradiation in vitro, and Ft-H overexpression increased the efficacy of chemoradiation in vivo in H1299. These results support the hypothesis that the depletion of the LIP can induce genomic instability, cell death, and potentiate therapeutic responses to chemoradiation in NSCLC.

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Section: Discussionmentioning

confidence: 99%

Depletion of Labile Iron Induces Replication Stress and Enhances Responses to Chemoradiation in Non-Small-Cell Lung Cancer

Bayanbold,

Singhania,

Fath

et al. 2023

Antioxidants

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“…The activity of the mitochondrial cysteine desulfurase NFS1 is required not only for mitochondrial but also for extra-mitochondrial Fe-S protein biogenesis which in addition involves the CIA (cytosolic Fe-S protein assembly) machinery 21,22 . We therefore tested whether D-Cys would affect the levels of cytosolic and/or nuclear Fe-S proteins involved in nucleotide metabolism, genome integrity, and iron regulation since in the apoform these proteins become unstable and are degraded 23,24 . Immunoblotting revealed a diminution of glutamine phosphoribosyl pyrophosphate amidotransferase (GPAT) 25 , dihydropyrimidine dehydrogenase (DPYD), DNA polymerase delta (POLD1), and Nth-like DNA glycosylase 1 (NTHL1) in D-Cys-treated A549 but not BEAS-2B cells, indicating a general defect in cytosolic and nuclear Fe-S protein assembly in A549 cells (Fig.…”

Section: D-cys Affects Cytosolic and Nuclear Fe-s Proteinsmentioning

confidence: 99%

D-cysteine inhibits iron-sulfur cluster assembly and impairs tumour growth

Martinou,

Zangari,

Stehling

et al. 2023

Preprint

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Selective targeting of cancer cells is a major challenge for cancer therapy. Many cancer cells overexpress the cystine/glutamate antiporter xCT/CD98 to increase the import of L-cystine for antioxidant defense, thus supporting tumour cell survival and progression1,2. We have exploited this feature of cancer cells by transforming xCT/CD98 overexpression into a selective vulnerability. We found that the D-enantiomer of cysteine (Cys), but not other D-amino acids, impaired proliferation of numerous xCT/CD98-expressing cancer cell lines, whereas xCT/CD98-non-overexpressing (cancer) cells were unaffected. D-Cys acquired by xCT/CD98 specifically inhibited the cysteine desulfurase NFS1, the sulfur donor of cellular iron-sulfur protein biogenesis3. NFS1 was able to form the D-Cys-ketimine intermediate, but, due to steric incompatibility, failed to transfer the D-Cys sulfur to its active-site Cys381 residue, thereby blocking enzymatic activity. This led to a general defect of all cellular processes relying on iron-sulfur proteins, including mitochondrial respiration, nucleotide metabolism, and nuclear genome maintenance, resulting in reduced oxygen consumption, accumulation of DNA damage, and cell cycle arrest. In vivo D-Cys administration diminished tumour growth of human triple-negative breast cancer cells implanted orthotopically into the mouse mammary gland. Hence, D-Cys could represent a simple therapy to selectively target those forms of cancer characterized by overexpression of xCT/CD98.

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