Anaphase lag
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Anaphase lag is a consequence of an event during cell division where sister chromatids do not properly separate from each other because of improper spindle formation.[1] The chromosome or chromatid does not properly migrate during anaphase and the daughter cells will lose some genetic information. It is one of many causes of aneuploidy. This event can occur during both meiosis and mitosis with unique repercussions. In either case, anaphase lag will cause one daughter cell to receive a complete set of chromosomes while the other lacks one paired set of chromosomes, creating a form of monosomy.[2] Whether the cell survives depends on which sister chromatid was lost and the background genomic state of the cell. The passage of abnormal numbers of chromosomes will have unique consequences with regard to mosaicism and development as well as the progression and heterogeneity of cancers.[3]
There are two notable mechanisms that cause Anaphase Lag, each of which are characterized by merotelic attachments of kinetochores to the microtubules responsible for chromatid separation.[4] Merotelic attachments occur when a single centromere kinetochore attaches to microtubules originating from both spindle poles of the dividing cell. The merotelic attachments can occur in two ways: centrosome spindle attachments from both poles on the same chromatid kinetochore[5] or the formation of a third centrosome whose microtubule spindles attach to a chromatid kinetochore.[6] Because the chromatid is being pulled in two opposing directions or away from the correct centriole, it cannot migrate to the mass of segregated chromatids at either pole. If the migration is significantly delayed the reformation of nuclei will begin to occur without a full complement of chromosomes. This nuclear envelope formation is also seen for the lone lagging sister chromatid, forming a micronucleus. The micronucleus has the capacity to persist in the daughter cell but with abnormal replication and maintenance machinery. This allows for the accumulation of mutations, increasing the potential for future miss-segregation events.[2] In total these events cause problematic aneuploid cells with increased genomic instability. This has important implications in the development and persistence of cancers as well as debilitating developmental diseases.[7]
Hallmark of cancer
One of the hallmarks of cancer formation and persistence is genomic instability, referring to the increased frequency in sequence mutation, chromosome rearrangement, and aneuploidy.[8] The instability allows a cancerous growth to increasingly diverge from normal cell growth and division, with the potential to gain new traits such as angiogenesis, immune system evasion, and loss of cell cycle checkpoint genes. Aneuploidy is a drastic divergence from the normal karyotype, as such the potential heterogeneity within these cells makes diagnosis and treatment increasingly difficult.[7]