Emergent Mitotic Chromosome Motions from a Changing Intracellular pH

The mechanism by which chromosomes establish and maintain a dynamic coupling to microtubules for force generation during the complex motions of mitosis remains elusive. Equally challenging is an explanation for the timing of poleward, antipoleward, and oscillatory chromosome movements. The molecular cell biology paradigm requires that specific molecules, or molecular geometries, for force generation are necessary for chromosome motions. We propose here that the dynamics of mitotic chromosome motions are an emergent property of a changing intracellular pH in combination with electrostatic forces. We explain this mechanism within the context of Complexity Theory, based on the electrostatic properties of tubulin, known cellular electric charge distributions, and the dynamic instability of microtubules.

Electrostatic Contributions to Carcinogenesis

Nanoscale electrostatics plays important roles in aster (spindle) assembly and motion, nuclear envelope breakdown and reassembly, and in force generation at kinetochores, poles, and chromosome arms for prometaphase, metaphase, and anaphase—A chromosome motions during mitosis. A large body of experimental evidence also suggests a role for electrostatics as the trigger for mitosis, which is considered here particularly in the context of cancer. Cancer cells are characterized by impaired intercellular electrical communication and adhesive contact as well as a loss of contact inhibition, conditions associated with increased cell surface negativity relative to their normal counterparts. Dividing cells have also been associated with lower transmembrane potentials and altered intracellular ionic concentrations. Here we propose that cancer cells are distinguished by abnormal trans- and intramembrane electric potentials, leading to the loss of active Na+/K+ plasma membrane pumping, increased intracellular concentrations of sodium and other ions, and alkaline nucleo-cytoplasmic pH, all of which are associated with and integral to carcinogenesis.

Electrostatic Mechanism for Depolymerization-Based Poleward Force Generation at Kinetochores

Experiments implicating bound volume positive charge at kinetochores interacting with negative charge at microtubule free ends have prompted our calculation of the force at kinetochores for chromosome poleward motility during mitosis. We present here a corroborating force calculation between positively charged Hec1 tails in kinetochores and negatively charged C-termini at microtubule free ends. Based on experimentally-known charge magnitudes on Hec1 tails and C-termini at microtubule free ends, an ab initio calculation of poleward (tension) force per microtubule that falls within the experimental range is demonstrated. Due to the locations of C-termini charges on concave sides of splaying microtubules, this attractive force between subsets of low curvature splaying microtubule protofilaments C-termini eventually fails for subsets of protofilaments with more pronounced curvature, thus generating poleward force as microtubules depolymerize in a dynamic coupling, as observed experimentally. The mechanism by which kinetochores establish and maintain a dynamic coupling to microtubules for force production during the complex motions of mitosis remains elusive, and force generation at kinetochores has emerged as a signature problem in chromosome motility. In agreement with experiment, two separate calculations show that attractive electrostatic interactions over nanometer distances account for poleward chromosome forces at kinetochores.