Presentation Title

A Novel Role of Histones in the Reduction and Provision of Copper for Mitochondrial Respiration and Superoxide Dismutase Function

Faculty Mentor

Siavash Kurdistani

Start Date

17-11-2018 10:00 AM

End Date

17-11-2018 10:15 AM

Location

C164

Session

Oral 2

Type of Presentation

Oral Talk

Subject Area

biological_agricultural_sciences

Abstract

The eukaryotic genome is packaged by histones that compact the genome and regulate DNA-based processes through histone tails and post-translational modifications. This study investigates a new purpose for the histone H3-H4 tetramer as a copper reductase that affects copper and iron homeostasis. The Kurdistani lab generated a mutation in residue 113, converting histidine to asparagine (H113N). It was observed that H113N defects can be rescued by increasing copper content, suggesting that the function of histone H3 is to optimize copper utilization. Copper is vital for the function of cytochrome c oxidase(Complex IV) in the electron transport chain via the cox17 chaperone protein. Copper is also known to regulate high affinity iron uptake, through the fet3 and fet5 genes in yeast. Copper is needed as well for superoxide dismutase function, sod1. It was hypothesized that histones would thus regulate copper and iron homeostasis by controlling the copper levels used for Complex IV, iron uptake, and sod1 function. Oxygen consumption assays showed the H113N mutation had reduced respiration that was recovered by 50 µM CuSO₄. Also, the H113N mutation increased sensitivity to iron depletion, induced by BPS, an iron chelator, or by an alkaline environment in growth assays. Using PCR-mediated gene deletion, it was discovered that the defect in iron homeostasis is not due to fet3 or fet5. Further experimentation proved that sod1 is responsible for the defection in iron homeostasis for histones, because addition of 1 μM Cu recovered H113N in the various sod1 deletion backgrounds. Through inductively coupled plasma mass spectrometry, it was confirmed that H113N has similar levels of copper and iron, supporting the idea that the defect is due to sod1 dysfunction. This study helps determine the unprecedented idea that histones provide reduced copper to the cell and has implications in both copper and iron homeostasis.

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Nov 17th, 10:00 AM Nov 17th, 10:15 AM

A Novel Role of Histones in the Reduction and Provision of Copper for Mitochondrial Respiration and Superoxide Dismutase Function

C164

The eukaryotic genome is packaged by histones that compact the genome and regulate DNA-based processes through histone tails and post-translational modifications. This study investigates a new purpose for the histone H3-H4 tetramer as a copper reductase that affects copper and iron homeostasis. The Kurdistani lab generated a mutation in residue 113, converting histidine to asparagine (H113N). It was observed that H113N defects can be rescued by increasing copper content, suggesting that the function of histone H3 is to optimize copper utilization. Copper is vital for the function of cytochrome c oxidase(Complex IV) in the electron transport chain via the cox17 chaperone protein. Copper is also known to regulate high affinity iron uptake, through the fet3 and fet5 genes in yeast. Copper is needed as well for superoxide dismutase function, sod1. It was hypothesized that histones would thus regulate copper and iron homeostasis by controlling the copper levels used for Complex IV, iron uptake, and sod1 function. Oxygen consumption assays showed the H113N mutation had reduced respiration that was recovered by 50 µM CuSO₄. Also, the H113N mutation increased sensitivity to iron depletion, induced by BPS, an iron chelator, or by an alkaline environment in growth assays. Using PCR-mediated gene deletion, it was discovered that the defect in iron homeostasis is not due to fet3 or fet5. Further experimentation proved that sod1 is responsible for the defection in iron homeostasis for histones, because addition of 1 μM Cu recovered H113N in the various sod1 deletion backgrounds. Through inductively coupled plasma mass spectrometry, it was confirmed that H113N has similar levels of copper and iron, supporting the idea that the defect is due to sod1 dysfunction. This study helps determine the unprecedented idea that histones provide reduced copper to the cell and has implications in both copper and iron homeostasis.