Biomedical Research

Replicative Crisis: Mapping Cellular Fates and Identifying Determinants between Cell Survival and Death

In order to divide indefinitely, most cancerous cells activate the enzyme telomerase, which elongates telomeres. To express telomerase, cells typically survive a state known as replicative crisis. This work explores two areas critical to understanding crisis-related mechanisms: the generation of chromosomal aberrations and cytosolic DNA species during crisis and determinants of cell death versus survival during crisis. Understanding these domains is critical to understanding the process of cancer cell immortalization.

By Ania Grodsky

Published 11:00 PM EST, Tues May 4, 2021


In order to divide indefinitely, most cancerous cells activate the enzyme telomerase, which elongates telomeres. To express telomerase, cells typically survive a state known as replicative crisis. Cells in crisis divide abnormally, promoting the generation of chromosomal rearrangements and cytosolic DNA species (micronuclei and chromatin bridges). These anomalies lead the cell towards one of two fates: survival through chromosomal aberrations that promote telomerase activation, or cell death through the detection of cytosolic DNA by cGAS. This mechanism of cell death may be circumvented by the exonuclease TREX1, which degrades cytosolic DNA prior to cGAS activation. Nearly all cells die during crisis; the possibility that a cell will activate telomerase through chromosomal aberrations is extremely small. This work explores two areas critical to understanding crisis-related mechanisms: the generation of chromosomal aberrations and cytosolic DNA species during crisis and determinants of cell death versus survival during crisis. Understanding these domains is critical to understanding the process of cancer cell immortalization.


The first section of this paper will discuss pathways and potential cell fates during crisis. Included in this review is a figure depicting possible stages and outcomes of cells in crisis. In order to understand crisis intermediate steps and outcomes, it is critical to understand the mechanism through which cells enter crisis.

Entering Crisis

Telomeres, the ends of chromosomes, consist of non-coding TTAGGG nucleotide repeats that shorten each time the cell divides. When telomeres become critically short, cellular senescence is initiated by the p53-dependent ATM kinase pathway. This process establishes the Hayflick limit, which states that cells can divide 40 – 60 times before becoming senescent.

However, in cells lacking p53, critically short telomeres cannot execute the ATM kinase pathway to promote senescence (Maciejowski and de Lange 2017). Instead, telomeres continue to shorten to the point that they are physically unable to hold TRF2, a telomeric protein critical to preventing telomere fusions. Chromosomes consequently fuse due to non-homologous end joining pathways. During anaphase, fused chromosomes are drawn to opposite poles of the cell. These chromosomes then pull on each other and form a bridge-like structure known as a chromatin bridge (CB).

This state of fused telomeres and chromatin bridges propels the cell into a state known as replicative crisis, which acts as the final tumor suppressor before cell immortalization. Crisis is best characterized by chromosomal instability; chromosomal aberrations, aneuploidy, and cytosolic DNA species are common (Nassour et al. 2019). 

Ultimately, however, crisis causes mass cell death (Maciejowski and de Lange 2017). Very rarely, a cell survives crisis by activating the tert gene, which encodes the enzyme telomerase. Telomerase adds TTAGGG repeats to the end of the telomere. With this gene active, cancer cells are able to thwart the Hayflick limit and proliferate indefinitely.

In this study, I will discuss various cell fates succeeding CB formation and the impact of these fates on cell survival. I will also review specific chromosomal aberrations that arise during crisis and are linked to telomerase activation

cGAS and TREX1

The second section of this paper will discuss the consequences of cGAS versus TREX1 binding to cytosolic DNA during crisis. Crisis generates cytosolic DNA species such as micronuclei and chromatin bridges (Maciejowski et al. 2015, Nassour et al. 2019). These structures typically have unstable nuclear envelopes prone to rupture (Maciejowski et al. 2015, Hatch et al. 2013, Nassour et al. 2019), consequently exposing DNA to the cytosol and cytosolic DNA-sensing enzymes cGAS and TREX1. cGAS and TREX1 bind competitively (Ablasser et al. 2014) and are critical to determining cell fate.

cGAS most commonly triggers an inflammatory response upon detection of cytosolic DNA by activating STING, which phosphorylates IRF3, ultimately causing the production of type I interferons (Motwani et al. 2019). This pathway is referred to as cGAS-STING. It is important to note that cGAS cannot distinguish between foreign and non-foreign DNA (Chen et al. 2016). In occurrences of invading DNA from agents such as viruses, cGAS may prove useful. However, if self-DNA is released from the nucleus, cGAS may trigger an unnecessary inflammatory response.

To prevent self-DNA from triggering cGAS-STING, the cell employs two defensive mechanisms: RPA and Rad51, as well as TREX1 (Wolf et al. 2019). RPA and Rad51, components of the DNA damage response system, bind to small fragments of ssDNA to prevent them from leaking out of the nucleus through nuclear pores. TREX1, a 3’ exonuclease, quickly degrades any DNA that manages to escape the nucleus. TREX1 is a membrane-bound endoplasmic reticulum (ER) protein (TREX1 – Three-Prime Repair Exonuclease 1); its exonuclease domain is located at the N-terminus and is exposed to the cytosol (Lehtinen et al. 2008), while the C-terminus attaches the protein to the ER (Chowdhury et al. 2006). Because of its location in the ER, TREX1 has near-immediate access to any exiting DNA.

The cGAS-STING pathway has recently been found to promote autophagic cell death in cells undergoing crisis (Nassour et al. 2019). TREX1 therefore promotes cell survival by preventing cGAS activation, as seen in Maciejowski and de Lange 2015 and Mohr et al. 2020. However, TREX1 seems to typically bind prior to cGAS to cytosolic DNA (Wolf et al. 2019, Mohr et al. 2020). It is therefore critical to determine why cGAS-mediated death is widespread during crisis.

In this study, in addition to pathways through crisis, I will discuss potential determinants of cGAS versus TREX1 binding to cytosolic DNA species and will specify topics that require additional research.

Pathways through Crisis

The first critical hallmark of crisis is CB formation. CBs have two possible fates during crisis: breakage and persistence (Maciejowski and de Lange 2017).

Fates Following CB Breakage

Bridges are prone to breakage within 1mb of the telomeres (the location of fusion) and at various fragile sites scattered throughout the genome (Lo et al. 2002, Hellman et al. 2002). CB breakage is most commonly followed by breakage-fusion-bridge (BFB) cycles (Guo et al. 2019). These cycles often result in regional amplifications; uneven breakage causes the now-larger chromosome to contain two copies of the gene(s) surrounding the breakage site. Genes near the ends of the chromosome or near fragile sites are prone to amplification.

Regionally amplified sequences may remain in the DNA, but may also cause double minute (DM) formation (Maciejowski and de Lange 2017). DMs are small, extrachromosomal, circular DNA fragments that lack regulatory elements. DM formation from normally repressed genes, such as tert, provides these genes with a greater chance of expression (the DNA is likely still regulated epigenetically). DMs have three primary fates: replication and further amplification of the gene (Ly and Cleveland 2017), which could enhance oncogene expression; reintegration into other locations in the genome, which causes chromosomal rearrangements; or nuclear bud formation (Fenech et al. 2010). Nuclear buds may detach from the nucleus to form micronuclei (MN). Consequences of MN will be discussed in a subsequent section.
Two mechanisms exist to terminate BFB cycles: break-induced replication and telomerase healing. Break-induced replication translocates the equivalent missing fragment (in size and location) of one chromosome to the chromosome undergoing BFB. These translocations are most frequently nonreciprocal (Murnane 2006) and may cause chromosomal rearrangements that interfere with existing gene regulation by enhancers and repressors. Telomerase healing may also interrupt BFB cycles (Maciejowski and de Lange 2017). Telomerase healing occurs spontaneously upon bridge breakage that results in complete loss of telomeres (Greider et. al 1994) and most commonly results in deletions and loss of heterozygosity (LOH) (Maciejowski and de Lange 2017).

MN may be generated if some fragments of the broken CB are not incorporated into the daughter nuclei. However, MN experience numerous issues with nuclear envelope (NE) assembly. MN only assemble “core” proteins, proteins found within the spindle region during division. “Non-core” proteins, found outside the spindle region do not assemble. The nuclear pore complex fails to assemble as well (Liu et al. 2018). Hatch et al. 2013 reported Lamin B1 deficiencies in MN and attributed the issue to an incomplete nuclear envelope formation process. Lamin B2 and A/C deficiencies have also been discovered (Petsalaki et al. 2016, Nassour et al. 2019).

MN NE instability cannot successfully be resolved by primary NE repair mechanisms. In primary NE repair, ER tubules/sheets spread around chromatin at the ruptured area to form a new NE, but in MN, these tubules/sheets physically invade the chromatin (Hatch et al. 2013). Because TREX1 is bound to the ER, it is able to interact with the chromatin upon invasion. This interaction is dependent on TREX1’s c-terminus anchorage to the membrane; TREX1 with mutated c-terminal domains do not degrade MN DNA (Mohr et al. 2020). TREX1 consequently degrades the DNA. 

Chromothripsis (chromosome fragmentation and random, highly error-prone repair of the resulting fragments) has been reported in MN (Zhang et al. 2015), but chromothripsis in MN has not been linked to TREX1. TREX1 is known to cause chromothripsis in CBs (Maciejowski et. al 2015). Based on Mohr et al. 2020’s and Maciejowski et al. 2015’s observations, it is likely that TREX1 causes chromothripsis in MN. Still, this finding has not yet been formally reported. If this theory proves to be correct, the post-chromothriptic MN may then be re-incorporated into the primary nucleus, where transcriptional activity on these chromosomes may increase (transcriptional activity in MN is highly disputed [Guo et al. 2019]). 

However, if TREX1 fails to degrade the exposed DNA, cGAS binding and cGAS-STING activation may occur. As observed in Nassour et al. 2019, this has the potential to lead to death through autophagic cell death.

If the MN resulting from CB breakage have substantial lamin (which is possible, although less likely), the MN may persist, move to another cell, re-incorporate to the nucleus, or undergo chromosome pulverization and chromothripsis (Hintzsche et al. 2017). Researchers have reported conflicting information regarding the transcriptional activity in MN, and it is therefore unclear to what extent micronuclear DNA is transcribed (Guo et al. 2019). Persistence of MN may therefore affect the cell as do deletions and LOH or may have little impact at all. The impacts of MN relocation between cells are also dependent on transcriptional activity. Re-incorporation has little impact unless the MN is re-incorporated into a new chromosomal location, where it could interfere with normal enhancer and repressor behavior.

Chromosome pulverization occurs when cell cycle signals from the primary nucleus influence the cell cycle process within MN, forcing MN to move forward in the cycle no matter their state of readiness (Guo et al. 2019). This results in premature chromosome condensation, which leads to chromosome pulverization. Chromothripsis follows, and the resulting fragments undergo error-prone repair that essentially randomly stitches fragments together. These scrambled chromosomes can be reincorporated into the primary nucleus during mitosis exit, leading to drastic genome rearrangements within the primary nucleus.

It has been reported that CB breakages lead to MN formation 70% of the time (Hoffelder et al. 2004). However, it has also been found that CB bridges lead to MN formation only 12.66% of the time (Rao et al. 2008). Although these numbers vary greatly, it is highly likely that cells in crisis will at some point form micronuclei. In the Nassour et al. 2019 simulation of crisis, IMR90 cells divided approximately 27 times (45-day crisis duration, approximately 40 hour cell doubling time [JCRB Cell Bank 2015]). Although Nassour et al. 2019’s crisis was simulated, the number of cell divisions is most likely not extremely different during actual crisis. It is therefore extremely likely that MN will be generated at some point (and multiple times) throughout crisis divisions.

Fates Following CB Persistence

Instead of breaking, the CB may continue to stretch until the NE undergoes transient rupture due to a lack of lamin to sufficiently enclose the chromatin (Maciejowski et al. 2015). In this scenario, chromothripsis ensues. During NE rupture, TREX1 enters the nucleus and degrades the CB into ssDNA. The bridge then splits to form two nuclear buds (Fenech et al. 2010). Each nuclear bud fuses with a daughter nucleus, allowing the fragments to return to a primary nucleus. Meanwhile, nuclear APOBEC enzymes mutate the ssDNA fragments. The ssDNA then undergo haphazard repair, generating a completely randomly arranged chromosome. Not all fragments are re-ligated together though; some are simply deleted, while others form double minutes (Ly and Cleveland 2017). Alternatively, if TREX1 is unable to degrade the DNA before cGAS detection, the cGAS-STING pathway becomes activated, possibly causing cell death (Nassour et al. 2019). However, although it seems logical that failed TREX1 degradation of CBs would lead to cGAS activation and death, cGAS-mediated death from CBs specifically has not been reported. cGAS has been shown to accumulate at CBs, though (Mohr et al. 2020).

Cell fusion can also occur if CBs do not break and sufficient lamin is available. This leads to tetraploidization (Pampalona et al. 2012). Because tetraploid cells have multiple centrioles, they undergo multipolar mitosis, which has a wide range of consequences (Pihan 2013). For instance, multipolar to bipolar spindle remodeling can occur. During this process, multiple centrioles align on the two poles of the cell as closely as possible to correct centriole positioning. This process consistently results in aneuploidy and commonly generates MN as well. Mitotic slippage and nucleokinesis without cytokinesis can also result from multipolar mitosis. Cells resulting from either of these processes are highly polyploid and are either mostly or completely incapable of division. The final two fates of multipolar mitosis are mitotic catastrophe and postmitotic apoptosis, both of which result in cell death.

Determinants of cell death versus cell survival during crisis

In most cases, TREX1 binds or attempts to bind prior to cGAS (Wolf et al. 2019, Mohr et al. 2020). In addition, cGAS-STING does not typically cause cell death; this pathway normally produces an inflammatory response. In non-crisis cells, autophagic removal of MN cells does not result in cell death (Rello-Varon et al. 2012). It is therefore critical to understand how mass cell death occurs during crisis by cGAS-STING-mediated autophagic cell death (ACD). Cell death by cGAS-STING is likely promoted by two elements: TREX1’s potential inability to sufficiently degrade DNA and altered cGAS-STING death promoting pathways.

TREX1’s Potential Inability to Sufficiently Degrade DNA

Oxidized DNA is resistant to TREX1 degradation (Gehrke et al. 2013). Reactive oxygen species (ROS) also cause increases in the levels of autophagy-related proteins p62 and LC3. Accumulation of ROS during crisis may therefore promote degradation by cGAS. Although ROS and crisis have not yet been studied, the following are speculatory sources of ROS generated by crisis:

  1. ROS may be generated as a result of aneuploidy. Due to significantly varied gene expression during aneuploidy, the frequency of misfolded proteins increases and places stress on the ER. This stress can trigger the unfolded protein response (UPR). UPR in turn causes mitochondrial stress and increased levels of ROS (Newman and Gregory 2019).
  2. NE rupture can cause PML bodies, which are involved in sensing oxidative stress in the nucleus, to move into the cytoplasm. This limits the nucleus’s ability to detect and respond to ROS. Similarly, mitochondria may also move inside the nucleus and generate ROS. The nucleus may reseal before the organelles can return to their proper cellular locations (Houthaeve et al. 2018).
  3. Lamin deficiencies can contribute to ROS generation and sensitivity. Lamin B deficiencies are more commonly observed (Hatch et al. 2013, Petsalaki et al. 2016), yet lamin A deficiencies have been reported as well (Nassour et al. 2019). Lamin A/C depletion is directly linked to oxidative stress by causing nuclei hypersensitivity to the effects of ROS (Houthaeve et al. 2018, Shimi and Godlman 2014). Lamin B depletion causes an increase of nucleoplasmic Oct-1, a protein that usually binds with Lamin B. Upon Oct-1 NE departure from the lamina, proteins that limit oxidative stress become downregulated (Malhas et al. 2019, Shimi and Goldman 2014).
  4. PARP activity is upregulated in cells with chromosomal instability (Khan et al. 2018). PARP activity depletes NAD+, causing mitochondrial stress and ROS generation (Murata et al. 2019).

Possible non-ROS related causes of cGAS activation generated by crisis are as follows:

  1. Because TREX1 interacts with PARP1 during DNA damage repair (Miyazaki et al. 2014), and PARP activity is upregulated in cells expressing features of chromosomal instability (Khan et al. 2018), TREX1 may have limited substrate availability during crisis.
  2. In MN specifically, because TREX1 tethering to the ER membrane is required for TREX1 resection of DNA (Mohr et al. 2020), a mechanism caused by ER stress (Newman and Gregory 2019) could potentially interfere with ER tubule invasion or TREX1 anchorage. 
  3. A mechanism may exist for TREX1 to detach and reattach to its c-terminus. This unknown mechanism may cause TREX1 to become detached from the ER during crisis. Mohr et al. 2020 found that TREX1 cannot degrade MN DNA if TREX1’s c-terminal domain is altered so that TREX1 is not bound to the ER. Since TREX1 is involved in PARP1 activity during DNA damage repair, TREX1 translocates to the nucleus. However, in order for TREX1 to enter, it must lose its c-terminus (Brucet et al. 2007). This mechanism could prevent TREX1 action in MN, but could also promote TREX1 activation on chromatin bridges (because TREX1 would already be inside the nucleus).
  4. The amount of DNA within the cytosolic formation may influence protein response as well. Some MN or CBs may simply contain too much DNA for TREX1 to successfully degrade before cGAS activation. Larger MN or longer CBs have so far not been specifically linked to crisis, but such a connection may exist. 
  5. The location of the MN could also play a role in determining protein response. In the nucleus NE, TREX1 binds preferentially to escaping DNA because of TREX1’s proximity to the nucleus (Wolf et al. 2019). MN located near the nucleus may be prone to TREX1 detection (because TREX1 is located in the ER), but MN farther from the nucleus may be prone to detection by cGAS. Further MN distance from the nucleus has not yet been associated with crisis, but it is possible that this relationship exists.

Altered cGAS-STING Pathway or Altered Pathway Impacts

Because cGAS-STING does not typically cause cell death, conditions within crisis cells may alter the cGAS-STING pathway and the impacts it has on the cell. However, very little is known about autophagic cell death, especially pertaining to cGAS-STING and crisis. This area requires much more research.

cGAS-STING has been reported to cause death by the NLRP3 inflammasome in myeloid cells (Gaidt et al. 2017). NLRP3 inflammasomes primarily exist in immune cells but have also been reported in some non-immune cells (Walenta et al. 2018). Although an NLRP3-based mechanism of death is unlikely, it should not be eliminated.

In a more general sense, cell survival of crisis requires telomerase activation. Because the chance of an aberration specifically activating telomerase is very rare, and cells exist in crisis until they activate telomerase or die, some cause of death is likely to arise before telomerase is activated. Even if these factors are not commonly found during some crisis, some factor (either listed or unlisted) is likely to be prevalent enough at some point during crisis cell divisions to promote cGAS activation and cGAS-STING-mediated death.


As crisis is a fairly novel field, there is limited understanding on the precise mechanisms of this state. Many questions remain, especially regarding determinants between cell survival and death. To conclude, I will present my recommendations for specific crisis-related mechanisms that should be investigated more thoroughly.

Research concerning whether or not ROS are present in cells undergoing crisis is critical because there are numerous plausible causes of ROS generation during crisis (discussed above). If ROS are present, other relevant investigations can be conducted based on the possible origins of ROS listed above. Other important research areas regarding TREX1 and cGAS binding during crisis include TREX1 and PARP1 interactions during crisis, ER stress and its impact on ER tubule invasion, the mechanism of TREX1 c-terminus loss and whether or not this mechanism occurs during crisis, the size of MN and the corresponding likelihood of cGAS-STING activation, and the proximity to nucleus of MN and the corresponding likelihood of cGAS-STING activation.

As mentioned previously, significantly more research is required regarding how cGAS-STING causes death in crisis cells. Although ACD is suggested, ACD does not occur in non-crisis cells (Rello-Varon et al. 2012). Factors that promote ACD in crisis cells require additional research as well. Although possibly less important, research on the role (if any) of inflammasomes in crisis may help uncover possible mechanisms of cell death, as well.

In regards to pathways through crisis, further research defining the mechanisms of TREX1 action is needed. TREX1 action in MN is ER-dependent, while TREX1 action on CBs requires that TREX1 detach from its c-terminus. Research regarding ER tubules during TREX1 invasion of transiently ruptured primary nuclei would be particularly enlightening.

Continuing research in this field is critical to understanding how cancer cells become immortal. When a thorough understanding of the crisis process is reached, work can begin to identify preventative measures against cell immortalization.


I primarily used Google Scholar to identify sources. To find articles on Google Scholar, I frequently used quote searches to find articles that include all desired words. This was particularly important because my work is centered on the topic crisis. Because the word crisis may also be used in various other contexts, the research included the word “telomere” in the search bar as well. This type of search was also useful to see if articles have been written demonstrating a connection between two or more phenomena (eg. lamin and ROS).

I frequently used articles from PubMed, Elsevier and Nature, but other databases and journals were used as well. I had access to database and journal subscriptions through a parent’s university account. Articles were selected based on to what extent they aligned with the research objectives. When searching for information within articles, I used ctrl f to find key words and the chrome extension Chrome Regex Search to locate multiple key words in one query. Chrome extensions Diigo and Weava were used to highlight and annotate articles.

Ania Grodsky, Youth Medical Journal 2021


Brucet, M., Querol-Audí, J., Serra, M., Ramirez-Espain, X., Bertlik, K., Ruiz, L., Lloberas, J., Macias, M. J., Fita, I., & Celada, A. (2007). Structure of the Dimeric Exonuclease TREX1 in Complex with DNA Displays a Proline-rich Binding Site for WW Domains. Journal of Biological Chemistry, 282(19), 14547–14557. 

Chen, Q., Sun, L., & Chen, Z. J. (2016). Regulation and function of the cGAS–STING pathway of cytosolic DNA sensing. Nature Immunology, 17(10), 1142–1149.

Chowdhury, D., Beresford, P. J., Zhu, P., Zhang, D., Sung, J.-S., Demple, B., Perrino, F. W., & Lieberman, J. (2006). The Exonuclease TREX1 Is in the SET Complex and Acts in Concert with NM23-H1 to Degrade DNA during Granzyme A-Mediated Cell Death. Molecular Cell, 23(1), 133–142. 

Ferber, M. J., Eilers, P., Schuuring, E., Fenton, J. A. L., Fleuren, G. J., Kenter, G., Szuhai, K., Smith, D. I., Raap, A. K., & Brink, A. A. T. P. (2004). Positioning of cervical carcinoma and Burkitt lymphoma translocation breakpoints with respect to the human papillomavirus integration cluster in FRA8C at 8q24.13. Cancer Genetics and Cytogenetics, 154(1), 1–9.

Fenech, M., Kirsch-Volders, M., Natarajan, A. T., Surralles, J., Crott, J. W., Parry, J., Norppa, H., Eastmond, D. A., Tucker, J. D., & Thomas, P. (2010). Molecular mechanisms of micronucleus, nucleoplasmic bridge and nuclear bud formation in mammalian and human cells. Mutagenesis, 26(1), 125–132.

Gaidt, M. M., Ebert, T. S., Chauhan, D., Ramshorn, K., Pinci, F., Zuber, S., O’Duill, F., Schmid-Burgk, J. L., Hoss, F., Buhmann, R., Wittmann, G., Latz, E., Subklewe, M., & Hornung, V. (2017). The DNA Inflammasome in Human Myeloid Cells Is Initiated by a STING-Cell Death Program Upstream of NLRP3. Cell, 171(5), 1110-1124.e18. 

Gehrke, N., Mertens, C., Zillinger, T., Wenzel, J., Bald, T., Zahn, S., Tüting, T., Hartmann, G., & Barchet, W. (2013). Oxidative Damage of DNA Confers Resistance to Cytosolic Nuclease TREX1 Degradation and Potentiates STING-Dependent Immune Sensing. Immunity, 39(3), 482–495. 

Greider, C. W. (1994). Mammalian telomere dynamics: healing, fragmentation shortening and stabilization. Current Opinion in Genetics & Development, 4(2), 203–211. 

Guo, X., Ni, J., Liang, Z., Xue, J., Fenech, M. F., & Wang, X. (2019). The molecular origins and pathophysiological consequences of micronuclei: New insights into an age-old problem. Mutation Research/Reviews in Mutation Research, 779, 1–35.

Hatch, E. M., Fischer, A. H., Deerinck, T. J., & Hetzer, M. W. (2013). Catastrophic Nuclear Envelope Collapse in Cancer Cell Micronuclei. Cell, 154(1), 47–60.

Hellman, A., Zlotorynski, E., Scherer, S. W., Cheung, J., Vincent, J. B., Smith, D. I., Trakhtenbrot, L., & Kerem, B. (2002). A role for common fragile site induction in amplification of human oncogenes. Cancer Cell, 1(1), 89–97.

Hintzsche, H., Hemmann, U., Poth, A., Utesch, D., Lott, J., & Stopper, H. (2017). Fate of micronuclei and micronucleated cells. Mutation Research/Reviews in Mutation Research, 771, 85–98. 

Hoffelder, D., Luo, L., Burke, N., Watkins, S., Gollin, S., & Saunders, W. (2004). Resolution of anaphase bridges in cancer cells. Chromosoma, 112(8).

Houthaeve, G., Robijns, J., Braeckmans, K., & Vos, W. H. D. (2018). Bypassing Border Control: Nuclear Envelope Rupture in Disease. Physiology, 33(1), 39–49. doi: 10.1152/physiol.00029.2017 

JCRB Cell Bank. (2015). -Detailed Information [JCRB9054]-. Nibiohn.Go.Jp.

Khan, M., Shaukat, Z., Saint, R., & Gregory, S. L. (2018). Chromosomal instability causes sensitivity to protein folding stress and ATP depletion. Biology Open, 7(10), bio038000. 

Lehtinen, D. A., Harvey, S., Mulcahy, M. J., Hollis, T., & Perrino, F. W. (2008). The TREX1 Double-stranded DNA Degradation Activity Is Defective in Dominant Mutations Associated with Autoimmune Disease. Journal of Biological Chemistry, 283(46), 31649–31656. 

Lo, A. W. l., Sabatier, L., Fouladi, B., Pottier, G., Ricoul, M., & Mumane, J. P. (2002). DNA Amplification by Breakage/Fusion/Bridge Cycles Initiated by Spontaneous Telomere Loss in a Human Cancer Cell Line. Neoplasia, 4(6), 531–538.

Ly, P., & Cleveland, D. W. (2017). Rebuilding Chromosomes After Catastrophe: Emerging Mechanisms of Chromothripsis. Trends in Cell Biology, 27(12), 917–930. 

Maciejowski, J., Li, Y., Bosco, N., Campbell, P. J., & de Lange, T. (2015). Chromothripsis and Kataegis Induced by Telomere Crisis. Cell, 163(7), 1641–1654. 

Maciejowski, J., & de Lange, T. (2017). Telomeres in cancer: tumour suppression and genome instability. Nature Reviews Molecular Cell Biology, 18(3), 175–186.

Malhas, A. N., Lee, C. F., & Vaux, D. J. (2009). Lamin B1 controls oxidative stress responses via Oct-1. Journal of Cell Biology, 184(1), 45–55. 

Mohr, L., Toufektchan, E., Chu, K., & Maciejowski, J. (2020). ER-directed TREX1 limits cGAS recognition of micronuclei.

Motwani, M., Pesiridis, S., & Fitzgerald, K. A. (2019). DNA sensing by the cGAS–STING pathway in health and disease. Nature Reviews Genetics, 20(11), 657–674.

Murata, M. M., Kong, X., Moncada, E., Chen, Y., Imamura, H., Wang, P., Berns, M. W., Yokomori, K., & Digman, M. A. (2019). NAD+ consumption by PARP1 in response to DNA damage triggers metabolic shift critical for damaged cell survival. Molecular Biology of the Cell, 30(20), 2584–2597. 

Murnane, J. P. (2006). Telomeres and chromosome instability. DNA Repair, 5(9–10), 1082–1092.

Nassour, J., Radford, R., Correia, A., Fusté, J. M., Schoell, B., Jauch, A., Shaw, R. J., & Karlseder, J. (2019). Autophagic cell death restricts chromosomal instability during replicative crisis. Nature, 565(7741), 659–663.

Newman, D. L., & Gregory, S. L. (2019). Co-Operation between Aneuploidy and Metabolic Changes in Driving Tumorigenesis. International Journal of Molecular Sciences, 20(18), 4611. 

Pampalona, J., Frías, C., Genescà, A., & Tusell, L. (2012). Progressive Telomere Dysfunction Causes Cytokinesis Failure and Leads to the Accumulation of Polyploid Cells. PLoS Genetics, 8(4), e1002679. 

Petsalaki, E., & Zachos, G. (2016). Clks 1, 2 and 4 prevent chromatin breakage by regulating the Aurora B-dependent abscission checkpoint. Nature Communications, 7(1). 

Pihan, G. A. (2013). Centrosome Dysfunction Contributes to Chromosome Instability, Chromoanagenesis, and Genome Reprograming in Cancer. Frontiers in Oncology, 3.

Rao, X., Zhang, Y., Yi, Q., Hou, H., Xu, B., Chu, L., Huang, Y., Zhang, W., Fenech, M., & Shi, Q. (2008). Multiple origins of spontaneously arising micronuclei in HeLa cells: Direct evidence from long-term live cell imaging. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 646(1–2), 41–49. 

Rello-Varona, S., Lissa, D., Shen, S., Niso-Santano, M., Senovilla, L., Mariño, G., Vitale, I., Jemaá, M., Harper, F., Pierron, G., Castedo, M., & Kroemer, G. (2012). Autophagic removal of micronuclei. Cell Cycle, 11(1), 170–176.

Shimi, T., & Goldman, R. D. (2014). Nuclear Lamins and Oxidative Stress in Cell Proliferation and Longevity. Cancer Biology and the Nuclear Envelope, 415–430.

Stingele, S., Stoehr, G., Peplowska, K., Cox, J., Mann, M., & Storchova, Z. (2012). Global analysis of genome, transcriptome and proteome reveals the response to aneuploidy in human cells. Molecular Systems Biology, 8(1), 608. 

TREX1 – Three-prime repair exonuclease 1 – Homo sapiens (Human) – TREX1 gene & protein. (2020). Uniprot.Org.

Valentijn, L. J., Koster, J., Zwijnenburg, D. A., Hasselt, N. E., van Sluis, P., Volckmann, R., van Noesel, M. M., George, R. E., Tytgat, G. A. M., Molenaar, J. J., & Versteeg, R. (2015). TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors. Nature Genetics, 47(12), 1411–1414.

Walenta, L., Schmid, N., Schwarzer, J. U., Köhn, F.-M., Urbanski, H. F., Behr, R., Strauss, L., Poutanen, M., & Mayerhofer, A. (2018). NLRP3 in somatic non-immune cells of rodent and primate testes. Reproduction, 156(3), 231–238. 

Wolf, C., Rapp, A., Berndt, N., Staroske, W., Schuster, M., Dobrick-Mattheuer, M., Kretschmer, S., König, N., Kurth, T., Wieczorek, D., Kast, K., Cardoso, M. C., Günther, C., & Lee-Kirsch, M. A. (2016). RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA. Nature Communications, 7(1). 

Yuan, X., Larsson, C., & Xu, D. (2019). Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players. Oncogene, 38(34), 6172–6183.

Zhang, C.-Z., Spektor, A., Cornils, H., Francis, J. M., Jackson, E. K., Liu, S., Meyerson, M., & Pellman, D. (2015). Chromothripsis from DNA damage in micronuclei. Nature, 522(7555), 179–184. 

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