Trends in Biochemical Sciences
ReviewHow Cells Respond to DNA Breaks in Mitosis
Section snippets
Differential Responses to DNA Breaks in Interphase and Mitosis
Cells must maintain genome stability during cycles of cell division to pass on their hereditary material intact to the next generation [1]. DNA is vulnerable to endogenous and exogenous sources of damage, so cells have evolved a complex network of biochemical pathways to counteract these threats, collectively called the DNA damage response (DDR). Activation of the DDR involves recognition and repair of DNA lesions, modulation of chromatin structure and transcription, and cell-cycle checkpoint
DNA Damage Checkpoint Signaling in Interphase and Mitosis
Many types of DNA damage can be repaired rapidly without the need for cells to activate cell-cycle checkpoints or sustain other global signaling responses. However, some lesions, such as DNA DSBs, are highly toxic and can be particularly challenging for cells to repair accurately without causing genome instability [1], especially if left unrepaired when cells attempt chromosome segregation during mitosis. The DDR is initiated by three structurally related protein kinases: ATM, ATR, and DNA-PKcs
DSB Repair and the Chromatin Response to DNA Breaks in Interphase and Mitosis
In interphase, most DSBs are repaired via the nonhomologous end-joining (NHEJ) or homologous recombination (HR) pathways [37]. NHEJ re-ligates DNA ends with limited or no DNA end processing and is the predominant DSB repair mechanism that cells use throughout interphase except at collapsed DNA replication forks, where NHEJ is highly toxic so HR pathways must be used instead [38,39]. HR pathways rely on the presence of a homologous donor template for the repair and accurate regeneration of the
Are DSBs Repaired in Mitosis?
The absence of 53BP1 recruitment to sites of DSBs in mitosis removes a major DNA-end resection roadblock that could, in theory, allow hyper-resection in mitosis. However, this is not observed in mitotic cells [77,78], possibly due to the fact that chromosomes are too highly condensed for enzymes involved in long-range resection to overcome. In addition to lack of DNA-end resection, key HR factors such as BRCA1 and RAD51 are also not recruited to mitotic DSB sites [30,79]. The bulk of evidence
Consequences of Defective Responses to DNA Breaks during Mitosis
If a DSB that occurs in mitosis fails to be repaired or tethered, the affected chromosome breaks into two pieces: an acentric chromosome fragment and a centric chromosome fragment, each containing a telomere on one end and free DNA end on the other (Figure 3). Since the acentric fragment is not able to interact with the mitotic spindle, it lingers near the equatorial plate during anaphase. These acentric fragments usually randomly segregate into the cytoplasm of one of the daughter cells and
Under-replicated DNA as an Endogenous Source of Mitotic DSBs
Due to the relative amount of time cells spend in mitosis compared with interphase, the majority of DSBs that cells acquire from exogenous sources would be expected to occur and be repaired in interphase. Clearly however, the fact that mitosis-specific DSB responses exist and are apparently conserved from some single-celled organisms to humans [15] means that DSBs must occur to a significant extent during cell division and be recognized for the maintenance of genome stability. What might the
Concluding Remarks
The key features of the specialized response to DNA breaks in mitosis can be summarized as follows. On entering prophase, cells do not arrest the cell cycle in the presence of DSBs and instead prioritize completion of cell division over repair of DNA breaks. The chromatin response to DSBs is truncated in mitosis. Although H2AX is phosphorylated in mitosis and recognized by MDC1, the recruitment of key downstream factors that regulate DSB repair pathway choice such as 53BP1 and BRCA1 is blocked.
Acknowledgments
Andrew Blackford is funded by a Cancer Research UK Career Development Fellowship (C29215/A20772). We apologize to all colleagues whose important findings could not be cited owing to space limitations.
Glossary
- Anaphase-promoting complex/cyclosome (APC/C)
- a multisubunit E3 ubiquitin ligase complex that targets various cell-cycle proteins for degradation by the proteasome and thus mainly regulates the metaphase-to-anaphase transition.
- Apoptosis
- a highly regulated and tightly controlled form of programmed cell death that occurs in multicellular organisms, mediated in response to DNA damage by the tumor suppressor p53.
- Cell-cycle checkpoints
- control mechanisms in eukaryotic cells that block or slow cell-cycle
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Cited by (43)
High turnover and rescue effect of XRCC1 in response to heavy charged particle radiation
2022, Biophysical JournalCitation Excerpt :Taking the accelerated dissociation from old damage and quicker recruitment of XRCC1 to new damage together, the XRCC1 demonstrates its recyclable capability in DDR and its rescue mechanism to process newly generated damage with high priority, whereas its role at the old repair factory has not been completed (discussed hereafter). The amount and organization of nuclear DNA are variant and metabolic through the cell cycle, impacting the DNA damages response and repair processes (31,32). To determine the influence of the cell cycle on the early XRCC1 response in the DDR process, HT1080 cells in the G1 phase and G2 phase were irradiated with 2150 MeV ions, and the XRCC1 kinetics was investigated.
Dual-functional significance of ATM-mediated phosphorylation of spindle assembly checkpoint component Bub3 in mitosis and the DNA damage response
2022, Journal of Biological ChemistryMechanisms of genome stability maintenance during cell division
2021, DNA RepairCitation Excerpt :In mitosis, DSBs are particularly dangerous lesions because they produce acentric chromosome fragments that cannot attach to the mitotic spindle. Moreover, DSB repair is thought to be at least partially inactive during mitosis (recently reviewed in [40]). Consistently, mitotic cells are highly sensitive to DSB-inducing agents such as ionizing radiation (IR) [41–44].
New Facets of DNA Double Strand Break Repair: Radiation Dose as Key Determinant of HR versus c-NHEJ Engagement
2023, International Journal of Molecular Sciences