Chromosome integrity checkpoints in stem and progenitor cells: transitions upon differentiation, pathogenesis, and aging

Abstract

Loss of chromosome integrity is a major contributor to cancer. Checkpoints within the cell division cycle that facilitate the accuracy and outcome of chromosome segregation are thus critical pathways for preserving chromosome integrity and preventing chromosomal instability. The spindle assembly checkpoint, the decatenation checkpoint and the post-mitotic tetraploidy checkpoint ensure the appropriate establishment of the spindle apparatus, block mitotic entry upon entanglement of chromosomes or prevent further progression of post-mitotic cells that display massive spindle defects. Most of our knowledge on these mechanisms originates from studies conducted in yeast, cancer cell lines and differentiated cells. Considering that in many instances cancer derives from transformed stem and progenitor cells, our knowledge on these checkpoints in these cells just started to emerge. With this review, we provide a general overview of the current knowledge of these checkpoints in embryonic as well as in adult stem and progenitor cells with a focus on the hematopoietic system and outline common mis-regulations of their function associated with cancer and leukemia. Most cancers are aging-associated diseases. We will thus also discuss changes in the function and outcome of these checkpoints upon aging of stem and progenitor cells.

Intermediate filaments and IF-associated proteins: from cell architecture to cell proliferation

“…Tetraploidy can cause chromosomal instability, thus providing a route to aneuploidy and contributing to the development of aging and cancer. 129,130) Loss of the tetraploidy checkpoint and subsequent catastrophic mitosis may lead to the generation of aneuploid cells. In fact, the expression of senescence-related genes was significantly increased in VIM SA/SA mice.…”

The lifespan quantitative trait locus gene Securin controls hematopoietic progenitor cell function

“…The proximal locus on chromosome 11, which spans about 18.6 Mb, is however the only region which is identical between both congenic mouse strains, making a substantial contribution of other loci less likely (Suppl. [25][26][27] The initial linkage data also imply a role for Pttg1 in regulating lifespan. The primary role of Pttg1 is an inhibition of Separase.…”

The Genomic Health of Human Pluripotent Stem Cells: Genomic Instability and the Consequences on Nuclear Organization

“…For correct chromosome segregation there are two critical checkpoints, known as the spindle assembly checkpoint and the decatenation checkpoint. The G1 tetraploidy checkpoint also assesses for chromosome aberration, especially additional chromosomes (Brown and Geiger, 2018). Very interestingly in murine ESCs the spindle assembly checkpoint was not activated as it would be in somatic cells, leading to apoptosis and so the possibility of a higher numbers of cells with aneuploidy (Rohrabaugh et al, 2008).…”