Intracellular pH as an electrostatic regulator of the spindle assembly checkpoint.

Abstract

Experiments have shown that intracellular pH of many cells rises to a maximum at the onset of mitosis, subsequently decreasing 0.3 to 0.5 pH units by the end of mitosis. This result, and observations that tubulin net charge depends strongly on pH, may be significant for microtubule (MT) dynamics during mitosis. In vivo studies demonstrate that MT dynamics is sensitive to pH, with MT growth favored by higher pH values. Thus it seems likely that the shift from the dominance of mi- crotubule growth during prophase, and to a lesser extent during prometaphase, to a parity between MT polymerization and depolymerization during metaphase chromo- some oscillations is a consequence of a gradually decreasing intracellular pH during mitosis. A long-standing problem in the cell biology of mitosis concerns the operation of the spindle assembly checkpoint, a surveillance mechanism that delays anaphase-A onset until all chromosomes are attached to the spindle. When improper chromosome attachments persist into anaphase, chromosome segregation is defective and cells con- taining abnormal numbers of chromosomes can result leading to genetic diseases such as cancer. Here we propose that a consequence of relatively high intracellular pH near the metaphase-anaphase transition results in an anaphase-A delay that functions as the spindle assembly checkpoint.