Centromeres split during anaphase, the phase of mitosis when sister chromatids are pulled apart and moved to opposite ends of the cell. This separation marks an irreversible commitment: once the centromere divides, the cell cannot go back. But the split itself is the final step in a tightly controlled sequence of events that begins well before anaphase starts.
What Happens at the Centromere During Anaphase
Throughout the earlier phases of mitosis, sister chromatids (the two identical copies of a chromosome) are physically glued together at the centromere by ring-shaped protein complexes called cohesins. These molecular clamps hold the paired chromatids in place while the cell’s spindle fibers attach to structures on the centromere called kinetochores. During anaphase, an enzyme slices through a key cohesin subunit, and the “glue” dissolves. The sister chromatids, no longer bound, are pulled toward opposite poles of the cell by spindle fibers that shorten as they disassemble.
The force behind this movement comes from the kinetochores themselves. They grip the tips of spindle microtubules and convert the energy released by microtubule disassembly into mechanical pulling force. Classic experiments measured this force decades ago by resisting chromosome movement with tiny glass needles, confirming that the spindle generates substantial tension on each chromatid.
The Safety Check Before Splitting
The cell doesn’t allow centromere splitting until every single chromosome is properly attached to spindle fibers from both poles. A surveillance system called the spindle assembly checkpoint monitors this. Even one unattached or tension-free kinetochore is enough to keep the checkpoint active and block the transition into anaphase.
Here’s how the block works. The checkpoint keeps a critical enzyme complex, the anaphase-promoting complex (APC/C), switched off. As long as the APC/C is inactive, a small inhibitor protein called securin stays intact and sits on top of the enzyme that would cut the cohesins. Securin physically blocks the active site of this cutting enzyme, called separase, like a key jammed in a lock. It even mimics features of the cohesin target to compete for separase’s attention, providing a second layer of inhibition beyond simply plugging the active site.
Once every chromosome is correctly attached and under tension from both spindle poles, the checkpoint shuts off. The APC/C activates and tags securin with a molecular destruction signal. The cell’s protein-recycling machinery then rapidly chews up securin, freeing separase. Now unleashed, separase cleaves a specific cohesin subunit at two precise sites (out of six possible target-like sequences on that subunit, only two are actually cut). The cohesins fall away, the centromere splits, and anaphase begins.
Why the Timing Is So Precise
This system is designed for an all-or-nothing switch. The checkpoint doesn’t gradually release; it holds firm until conditions are perfect, then releases all at once. This ensures that every centromere in the cell splits simultaneously. If some chromosomes separated before others, daughter cells could end up with the wrong number of chromosomes.
The kinetochore attachments themselves are also self-correcting. When a kinetochore attaches to the wrong spindle pole, creating no tension between sister chromatids, a signaling protein destabilizes that connection. The microtubule detaches, giving the kinetochore another chance to grab a fiber from the correct pole. Attachments under proper tension are stabilized through a catch-bond-like mechanism: the more pulling force applied, the longer the attachment lasts. This elegant feedback loop means that only correct, tension-bearing attachments survive long enough for the checkpoint to be satisfied.
How This Differs in Meiosis
In mitosis, the two kinetochores on a pair of sister chromatids face in opposite directions (back to back), so spindle fibers from opposite poles naturally grab one each. This is what makes anaphase pull the sisters apart.
Meiosis I works differently. Sister kinetochores are oriented side by side, facing the same direction. Special proteins force this arrangement so that both sisters travel together to the same pole during the first meiotic division. Centromeres do not split in meiosis I. Instead, it’s the connections between homologous chromosome pairs that are severed, reducing the chromosome number by half. Centromere splitting happens later, during meiosis II, which closely resembles a mitotic division. By meiosis II, the kinetochores have switched back to the back-to-back orientation, allowing sister chromatids to finally separate.
What Goes Wrong When Centromeres Don’t Split Correctly
When the splitting process fails, both sister chromatids can travel to the same pole, a mistake called nondisjunction. The result is one daughter cell with an extra chromosome and one missing a copy. This imbalance, called aneuploidy, is harmful in nearly every context.
In developing embryos, the consequences are severe. Gaining or losing most chromosomes is lethal before birth, causing the majority of first-trimester miscarriages. A few trisomies (three copies instead of two) are survivable but cause serious conditions: trisomy 21 causes Down syndrome, trisomy 18 causes Edwards syndrome, and trisomy 13 causes Patau syndrome. Sex chromosome imbalances are somewhat more tolerable. A missing X chromosome (45,X) causes Turner syndrome, and extra X chromosomes in males cause Klinefelter syndrome.
In adult tissues, chromosome segregation errors fuel cancer. Aneuploid cells have altered gene dosages that can drive uncontrolled growth, drug resistance, and increased malignancy. A rare condition called mosaic variegated aneuploidy, caused by mutations in a checkpoint gene, produces widespread aneuploidy across body tissues and leads to growth defects, abnormally small head size, and sharply increased cancer risk. Even in otherwise healthy cells, a failed separation can cause a chromosome to be physically torn by the spindle or by the pinching of cell division, creating broken fragments that may reattach to wrong chromosomes and produce deletions, duplications, or translocations.
If both the chromosome separation and cell division fail entirely, the cell doesn’t divide at all and becomes tetraploid, carrying a full double set of chromosomes. Tetraploid cells are genetically unstable and represent another common stepping stone toward cancer.