18.10: Forces Acting on Chromosomes

During mitosis, chromosome movements occur through the interplay of multiple piconewton level forces. In prometaphase, these forces help in chromosome assembly or congression at the equatorial plane, eventually leading to their alignment at the metaphase plate. The forces acting on the chromosomes are space and time-dependent; therefore, they vary with the position of the chromosomes as the cell progresses through mitosis.

Microtubules and motor proteins exert two types of forces on chromosomes—poleward and anti-poleward, also known as polar-ejection forces. Kinetochore microtubule depolymerization generates the poleward force and pulls the chromosome towards the spindle pole. In contrast, polymerization of the kinetochore-microtubule leads to polar-ejection forces, which push the chromosome towards the cell’s equator. Microtubule plus-end directed motor proteins, like chromokinesins and kinesin-7, also produce polar-ejection forces by propelling chromosomes towards the cell’s equator.

The simultaneous but unequal action of poleward and polar-ejection forces cause the oscillation of chromosomes during prometaphase; however, during metaphase, the bioriented sister chromatids experience equal but opposing forces. This creates enough tension to silence the spindle assembly checkpoint pathway and allows cells to move into anaphase. In anaphase, poleward forces act on sister chromatids, resulting in their successful segregation to the daughter cells.

In addition to the above forces, chromosomes are also subjected to cohesive and resolving forces. The cohesive force exerted by cohesin holds the sister chromatids together until the end of the metaphase. On the other hand, the resolving force generated by condensins allows chromosomes to form distinct rod-shaped structures, which helps in their proper separation during anaphase.

During mitosis, the bioriented chromosomes oscillate to stabilize their spindle attachments and subsequently assemble along the metaphase plate at the equator of the mitotic spindle.

Multiple forces act on chromosomes after they are attached to the mitotic spindle.

A major poleward force exerted along the kinetochore-microtubule, as a result of plus-end de-polymerization, pulls the kinetochore and its associated chromosome towards the spindle pole. At the kinetochore, Ndc80 protein complexes link the kinetochore to the microtubule through multiple low-affinity attachments along microtubule sides.

During microtubule plus-end de-polymerization, the Ndc80 attachments break and reform at new sites to maintain the kinetochore-microtubule connection. The mechanism gradually pulls the chromosome towards the spindle pole, as the microtubule shortens in length.

A second poleward force results from microtubule flux. Microtubule minus-end depolymerization generates a minus-end directed flux, causing microtubule movement towards the spindle pole. Coordinating plus-end polymerization compensates for the minus-end depolymerization, allowing microtubules to maintain their length.

A third force, ­the polar ejection force or polar wind, ­generated by kinesin-4 and 10 motor proteins pushes the chromosomes away from the spindle poles. Kinesin-4 and 10 link chromosomal arms with interpolar microtubules. These plus-end directed motor proteins move the chromosome toward the spindle equator.

A balanced interplay of these multiple opposing forces enables the bioriented chromosomes to precisely align along the metaphase plate, in preparation for chromosomal segregation.