Chromosome Segregation Defects in the Origin of Genomic Instability

Dear Colleagues,

The cell cycle, whose purpose is to become two where there was only one, is extraordinarily complex and tightly regulated. Any error in this process could cause an unsuccessful transmission of genetic material, leading from cancer to birth defects. A key stage during the cell cycle is anaphase, where an army of proteins gradually resolve, separate, and pull the sister chromatids to the daughter cells. Anaphase is particularly concerning as a source of genomic instability, since there are no good options for the cell to correctly deal with chromosome segregation errors (Figure 1).

Figure 1: Outcomes in diploid cells of the breakage and repair of anaphase bridges formed by unresolved sister chromatids (USC). A: The USC bridge just involves one homolog. B: The USC involves both homologs. Broken sisters are segregated symmetrically. C: Like in B but broken sisters are segregated asymmetrically. Further details in "Machín et al. Curr Genet. 2016; 62(1):7-13".

There are several genetically inherited human diseases, especially cancer-prone syndromes, that show chromosome segregation defects at the cellular level. In addition, many carcinogens and, paradoxically, clinically-used antitumor agents have a direct impact on the fidelity of chromosome transmission. Amongst the most common anaphase aberrations, we find chromatin and ultrafine anaphase bridges, lagging chromosomes, the breakage-fusion-bridge cycle, and chromosome nondisjunction. The physical causes of these aberrations include the unnatural presence of underreplicated chromosomes, unresolved recombination intermediates, topological constrains, proteinaceous linkages, multicentric chromosomes, telomere fusions, syntelyc/monotelyc attachments, and polycentrosomy. At a molecular level, mutations in numerous genes cause chromosome segregation defects, including those genes involved in DNA damage and replication checkpoints, the spindle assembly checkpoint, the structural maintenance of chromosomes (SMC) complexes (condensin, cohesin, and Smc5/6), topoisomerase II, DNA repair helicases, and structure-specific endonucleases.

In this Issue, we aim to gather a collection of reviews, research articles, and concept papers about the molecular players involved in the successful segregation of chromosomes, both in mitosis and meiosis, as well as manuscripts dealing with the instability footprints found in the progeny.

Kind regards,

Dr. Félix Machín
Guest Editor

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