Interrogating cell division errors using random and chromosome-specific missegregation approaches

ABSTRACT

Accurate segregation of the duplicated genome in mitosis is essential for maintaining genetic stability. Errors in this process can cause numerical and/or structural chromosome abnormalities – hallmark genomic features commonly associated with both tumorigenesis and developmental disorders. A cell-based approach was recently developed permitting inducible missegregation of the human Y chromosome by selectively disrupting kinetochore assembly onto the Y centromere. Although this strategy initially requires several steps of genetic manipulation, it is easy to use, highly efficient and specific for the Y without affecting the autosomes or the X, and does not require cell cycle synchronization or mitotic perturbation. Here we describe currently available tools for studying chromosome segregation errors, aneuploidy, and micronuclei, as well as discuss how the Y-specific missegregation system has been used to elucidate how chromosomal micronucleation can trigger a class of extensive rearrangements termed chromothripsis. The combinatorial use of these different tools will allow unresolved aspects of cell division defects and chromosomal instability to be experimentally explored.

KEYWORDS:

• aneuploidy
• centromere
• chromosome segregation
• chromothripsis
• micronuclei
• mitosis

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Funding

D.W.C was supported by NIGMS (R01 GM074150 and R35 GM122476) and receives salary support from the Ludwig Institute for Cancer Research. P.L. was supported by a Hope Funds for Cancer Research Postdoctoral Fellowship (HFCR-14–06–06).