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

Bakhoum, Samuel F.; Kabeche, Lilian; Compton, Duane A.; Powell, Simon N.; Bastians, Holger

doi:10.1016/j.trecan.2017.02.001

Cited by 63 publications

(52 citation statements)

References 64 publications

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“…Lagging chromosomes derived from unattached or mis-attached chromosomes, as well as from broken chromosomes lacking centromeric regions and kinetochore structures, produce structural alterations in cancer cells that result in whole chromosome gains and losses [25]. Lagging chromosomes can mis-segregate, leading to aneuploidy (i.e., numerical instability) and to translocations (i.e., structural instabilities) or can segregate as a form sequestered in micronuclei, which still results in effective aneuploidy [3]. A novel form of genetic instability known as "chromothripsis" is thought to be due, in part, to lagging chromosome pulverization [26,27].…”

Section: Discussionmentioning

confidence: 99%

“…In accordance, DNA damage response (DDR) protects genome stability by acting during the interphase of the cell cycle. Recently, it has been demonstrated that DDR is also involved in chromosome segregation during mitosis progression in normal cells (i.e., mitotic DDR) [3]. In addition, a huge array of data point out that cancer cells may acquire the ability of distorting the protective role of mitotic DDR.…”

Section: Discussionmentioning

confidence: 99%

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Depletion of Trichoplein (TpMs) Causes Chromosome Mis-Segregation, DNA Damage and Chromosome Instability in Cancer Cells

Lauriola

Martello

Fantini

et al. 2020

Cancers

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Mitotic perturbations frequently lead to chromosome mis-segregation that generates genome instability, thereby triggering tumor onset and/or progression. Error-free mitosis depends on fidelity-monitoring systems that ensure the temporal and spatial coordination of chromosome segregation. Recent investigations are focused on mitotic DNA damage response (DDR) and chromosome mis-segregations with the aim of developing more efficient anti-cancer therapies. We previously demonstrated that trichoplein keratin filament binding protein (TpMs) exhibits hallmarks of a tumor suppressor gene in cancer-derived cells and human tumors. Here, we show that silencing of TpMs expression results in chromosome mis-segregation, DNA damage and chromosomal instability. TpMs interacts with Mad2, and TpMs depletion results in decreased levels of Mad2 and Cyclin B1 proteins. All the genetic alterations observed are consistent with both defective activation of the spindle assembly checkpoint and mitotic progression. Thus, low levels of TpMs found in certain human tumors may contribute to cellular transformation by promoting genomic instability.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Depletion of Trichoplein (TpMs) Causes Chromosome Mis-Segregation, DNA Damage and Chromosome Instability in Cancer Cells

Lauriola

Martello

Fantini

et al. 2020

Cancers

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“…The vast majority of studies on DNA damage responses have been done during interphase of the cell cycle. However, understanding the DNA damage response (DDR) during mitosis is also important since mutations accumulated during mitosis can lead to chromosomal aberrations, genomic instability of daughter cells, senescence and eventual cell death [1–4].…”

Section: Introductionmentioning

confidence: 99%

DNA damage induced during mitosis undergoes DNA repair synthesis

Godinez

Kabbara

Cohen

et al. 2020

Preprint

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AbstractUnderstanding the mitotic DNA damage response (DDR) is critical to our comprehension of cancer, premature aging and developmental disorders which are marked by DNA repair deficiencies. In this study we use a micro-focused-laser to induce DNA damage in selected mitotic chromosomes to study the subsequent repair response. Our findings demonstrate that (1) mitotic cells are capable of DNA repair as evidenced by DNA synthesis at damage sites, (2) Repair is attenuated when DNA-PKcs and ATM are simultaneously compromised, (3) Laser damage may permit the observation of previously undetected DDR proteins when damage is elicited by other methods in mitosis, and (4) Twenty five percent of mitotic DNA-damaged cells undergo a subsequent mitosis. Together these findings suggest that mitotic DDR is more complex than previously thought and may involve factors from multiple repair pathways that are better understood in interphase.

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“…For instance, the signaling of ATR or ATM can keep the mitotic CDK1 kinase inactive through p53‐mediated expression of p21 WAF1/CIP1 or through CHEK1/CHEK2‐mediated activation of CDC25 proteins . Apart from such induced brakes to prevent mitotic entry, evidence has accumulated over the past years that several proteins involved in replication fork signaling and/or in DNA damage repair might also have central functions during the mitotic process in apparently undisturbed cells . It is largely unknown how their relative contributions to genome surveillance and to the regulation of mitotic progression are coupled.…”

Section: Introductionmentioning

confidence: 99%

“…3 Apart from such induced brakes to prevent mitotic entry, evidence has accumulated over the past years that several proteins involved in replication fork signaling and/or in DNA damage repair might also have central functions during the mitotic process in apparently undisturbed cells. [4][5][6][7][8][9] It is largely unknown how their relative contributions to genome surveillance and to the regulation of mitotic progression are coupled.…”

mentioning

confidence: 99%

RAD50 regulates mitotic progression independent of DNA repair functions

et al. 2019

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The Mre11A/RAD50/NBN complex (MRN) is an essential regulator of the cellular damage response after DNA double‐strand breaks (DSBs). More recent work has indicated that MRN may also impact on the duration of mitosis. We show here that RAD50‐deficient fibroblasts exhibit a marked delay in mitotic progression that can be rescued by lentiviral transduction of RAD50. The delay was observed throughout all mitotic phases in live cell imaging using GFP‐labeled H2B as a fluorescent marker. In complementation assays with RAD50 phosphorylation mutants, modifications at Ser635 had little effect on mitotic progression. By contrast with RAD50, fibroblast strains deficient in ATM or NBN did not show a significant slowing of mitotic progression. Ataxia‐telangiectasia‐like disorder (ATLD) fibroblasts with nuclease‐deficient MRE11A (p.W210C) tended to show slower mitosis, though by far not as significant as RAD50‐deficient cells. Inhibitor studies indicated that ATM kinase activity might not grossly impact on mitotic progression, while treatment with MRE11A inhibitor PFM39 modestly prolonged mitosis. Inhibition of ATR kinase significantly prolonged mitosis but this effect was mostly independent of RAD50 status. Taken together, our data unravel a mitotic role of RAD50 that can be separated from its known functions in DNA repair.

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

Cited by 63 publications

References 64 publications

Depletion of Trichoplein (TpMs) Causes Chromosome Mis-Segregation, DNA Damage and Chromosome Instability in Cancer Cells

Depletion of Trichoplein (TpMs) Causes Chromosome Mis-Segregation, DNA Damage and Chromosome Instability in Cancer Cells

DNA damage induced during mitosis undergoes DNA repair synthesis

RAD50 regulates mitotic progression independent of DNA repair functions

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