Perturbations in nucleosome structure from heavy metal association

Area of Science:

• Structural Biology
• Biochemistry
• Toxicology

Background:

• Heavy metals exhibit diverse biological roles, acting as essential nutrients, toxins, or therapeutic agents.
• Understanding heavy metal interactions with biological macromolecules like DNA and proteins is crucial for elucidating their effects.

Purpose of the Study:

• To investigate the binding preferences and structural impacts of various heavy metal cations on the nucleosome core particle.
• To elucidate the mechanisms by which specific heavy metals may influence genetic and epigenetic processes.

Main Methods:

• Crystallographic analysis was employed to determine the binding sites and interactions of heavy metal cations (Co(2+), Ni(2+), Rb(+), Cs(+), Mn(2+)) with the nucleosome core particle.
• Structural and sequence-dependent binding patterns were analyzed.

Main Results:

• Cobalt (Co(2+)) and nickel (Ni(2+)) preferentially bind to the DNA major groove in a sequence- and conformation-dependent manner.
• Rubidium (Rb(+)) and cesium (Cs(+)) cations bind opportunistically to DNA minor groove elements, particularly at AT dinucleotides.
• Co(2+) and Ni(2+) aggressively coordinate with guanine bases, inducing shifts in histone-DNA register and DNA structural changes, including base expulsion.
• These metals also bind to histone proteins, potentially cross-linking nucleosomes and coordinating with histidine residues.

Conclusions:

• The distinct binding modes and structural perturbations induced by Co(2+) and Ni(2+) suggest a role in carcinogenesis.
• Sustained binding and structural modulation by these heavy metals may impact genetic and epigenetic regulation, potentially contributing to cancer development.