Mitotic DNA Damage Response: At the Crossroads of Structural and Numerical Cancer Chromosome Instabilities
Authors: Samuel F. Bakhoum, Lilian Kabeche, Duane A. Compton, Simon N. Powell, Holger Bastians
Journal: Trends in cancer (2017)

The cellular DDR signaling and downstream DNA repair pathways are active in the cell cycle during interphase. Their role in mitosis has long remained unknown. Emerging evidence suggests that the many proteins involved in DNA repair are also required for the progression of normal mitosis and faithful chromosome segregation. Mitotic cells can experience DNA damage either exogenously from therapy or endogenously due to unrepaired premitotic damage. Emerging evidence shows that such damage can directly lead to errors in chromosome segregation. In normal cells, a mitotic DDR can serve to either mark damaged chromosomes for subsequent repair or induce p53-mediated cellular senescence to avoid the propagation of damaged genomes. Cancer cells coopt the mitotic DDR to further propagate chromosomal instability. This offers untapped therapeutic opportunities to target genomic instability in cancer. DNA double-strand breaks (DSBs) prevent cells from entering mitosis allowing cells to repair their genomic damage. Little is known about the response to DSBs once cells have already committed to mitosis. Here, we review the genome-protective role of the mitotic DNA damage response (DDR) and evidence suggesting that its untimely activation induces chromosome segregation errors and paradoxically undermines genomic integrity. In contrast to normal cells, cancer cells coopt this pathway to propagate structural and numerical chromosomal instabilities. Cells derived from genomically unstable tumors exhibit evidence for a partially activated DDR during mitosis, which leads to ongoing chromosome segregation errors. Thus, a thorough understanding of the consequences of mitotic DNA damage is key to our ability to devise novel anticancer therapeutic strategies. DNA double-strand breaks (DSBs) prevent cells from entering mitosis allowing cells to repair their genomic damage. Little is known about the response to DSBs once cells have already committed to mitosis. Here, we review the genome-protective role of the mitotic DNA damage response (DDR) and evidence suggesting that its untimely activation induces chromosome segregation errors and paradoxically undermines genomic integrity. In contrast to normal cells, cancer cells coopt this pathway to propagate structural and numerical chromosomal instabilities. Cells derived from genomically unstable tumors exhibit evidence for a partially activated DDR during mitosis, which leads to ongoing chromosome segregation errors. Thus, a thorough understanding of the consequences of mitotic DNA damage is key to our ability to devise novel anticancer therapeutic strategies. denotes continuous chromatin linking the two segregating masses; they can result from any number of causes: telomere fusion, chromosomal translocations causing dicentric chromosomes, broken centromeres, and incompletely replicated chromosomes. They are a hallmark of genomic instability and suggest a higher likelihood of premitotic genomic defects. a process by which chromosomes (or a part thereof) undergo multiple breaks with segmental loss and random repair leading to clustered complex rearranged regions in whole chromosomes or chromosome arms. one of the most important cell cycle checkpoints; it prevents cells from entering mitosis in the presence of DNA damage. a subset of microtubules that attach to kinetochores. These microtubules are among the most stable during mitosis; however, they exhibit dynamic behavior, constantly attaching and detaching from the kinetochores. This dynamic behavior is central to the cellular ability to correct erroneous attachments and prevent chromosome missegregation. Human kinetochores can bind an average of 26 microtubules. Cancer cells have defective kinetochore-microtubule release kinetics, often leading to chromosome segregation errors. large proteinaceous structures whose functions is to link spindle microtubules to mitotic chromosomes to achieve accurate chromosome segregation. They contain numerous proteins that act in concert to regulate the attachment and detachment rates of microtubules. a term used to describe chromosomes that, during anaphase, are erroneously attached to microtubules emanating from opposite spindle poles. They typically reside alone separately from the segregating chromosome masses. As a result, these chromosomes can segregate to the wrong daughter cells, become encapsulated into micronuclei, or experience structural damage. Lagging chromosomes are a hallmark of chromosomal instability in cancer and can be observed in both tumor-derived cell lines and fixed tumor samples. a conspicuous feature of cancer cells whereby they constantly undergo errors in chromosome segregation leading to unstable chromosome copy numbers (karyotypes) and intratumor heterogeneity. the process by which chromosomes frequently undergo structural alterations in their chromosomes, such as breaks and translocation.