Trends in Cancer
Volume 3, Issue 3, March 2017, Pages 225-234
Journal home page for Trends in Cancer

Review
Mitotic DNA Damage Response: At the Crossroads of Structural and Numerical Cancer Chromosome Instabilities

https://doi.org/10.1016/j.trecan.2017.02.001Get rights and content

Trends

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.

Section snippets

The Mitotic DNA Damage Response: Beyond Canonical DNA Repair

The primary function of mitosis is the faithful segregation of the genome into two copies that are equally shared among daughter cells. Mitotic cells are exquisitely sensitive to DNA DSBs 1, 2, 3, to which they can only mount a partial response that stops short of activating downstream DNA damage repair pathways [4] (Figure 1). While the compact architecture of mitotic chromatin is thought to confer a protective role, mitotic cells can still encounter DSBs as a result of persistent premitotic

The Genome Protective Role of the Mitotic DNA Damage Response

The fact that either the depletion of DDR elements or their aberrant activation during mitosis perturbs the process of faithful chromosome segregation demonstrates that this pathway has evolved to have a central role in mitotic genome segregation beyond its canonical function during interphase of the cell cycle. Emerging evidence suggests that the DDR exists in a semiactivated state during mitosis even in the absence of DNA damage [8] and that activation of some of its components is achieved

The Effect of DNA Damage Response Activation on Mitotic Timing

Beyond its role in marking sites of DNA damage, the consequences of activating the DDR during mitosis have remained elusive, and mounting evidence reveals it can paradoxically lead to deleterious effects on genome stability 6, 7. Partial induction of the DDR during mitosis perturbs several aspects of mitosis, including mitotic timing and anaphase chromosome segregation (Figure 2). Work in multiple species has linked DDR activation with a delay in mitotic progression (Figure 2B). DNA damage in

Putative Functions of the Mitotic DNA Damage Response in Normal Cells

The evolutionary relevance of mounting a partial DDR during mitosis, at a time when the cell is chiefly preoccupied with the process of chromosome segregation, is not clear. One possibility is that cells may need to address DNA damage during mitosis that arises from unrepaired DNA damage upon release from a G2/M checkpoint arrest. The G2/M checkpoint has an estimated threshold of 10–20 DSBs, below which cells can enter mitosis [26]. A second possibility is that cells need to address DNA damage

Mitotic DNA Damage in Cancer Cells: Linking Structural and Numerical Chromosomal Instabilities

Cancer cells can experience mitotic DNA damage as a result of accumulated premitotic damage from replication stress or a defective G2/M checkpoint 5, 6, 48. Alternatively, they can also experience de novo damage after cells, already committed to mitosis, are exposed to DNA-damaging therapies [41]. By inducing whole-chromosome segregation errors in response to mitotic damage, the DDR serves to link structural and numerical chromosome instabilities, which often co-exist in cancer. Lagging

Concluding Remarks

The role of the DDR during mitosis is only beginning to emerge, although it is clear that it does not simply mirror what is known about the DDR during interphase of the cell cycle (see Outstanding Questions). It is reasonable to postulate that the machinery responsible for safeguarding the genome during the G1, S, and G2 phases of the cell cycle would also be intimately involved in the intricate process of mitotic chromosome segregation. However, the purpose and hallmarks of this relationship

Acknowledgments

The authors would like to thank Kristina Godek for critical feedback and review of the manuscript. S.B. is supported by The Department of Defense Breast Cancer Research Breakthrough Award number W81XWH-16-1-0315, the Elsa U. Pardee Foundation, and the NCI MSKCC Cancer Center Core Grant. H.B. is supported by the Deutsche Forschungsgemeinschaft (DFG).

Glossary

Chromatin bridges
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.
Chromothripsis
a process by which chromosomes (or a part thereof) undergo multiple breaks with segmental loss and random repair

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