DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis

@article{Brtkov2005DNADR,
  title={DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis},
  author={Jiřina B{\'a}rtkov{\'a} and Zuzana Hořej{\vs}{\'i} and Karen Koed and Alwin Kr{\"a}mer and Fr{\'e}d{\'e}ric Tort and Karsten A E Zieger and Per Guldberg and Maxwell Sehested and Jahn Marthin Nesland and Claudia Lukas and Torben F. {\O}rntoft and Jiri Lukas and Jiri Bartek},
  journal={Nature},
  year={2005},
  volume={434},
  pages={864-870}
}
During the evolution of cancer, the incipient tumour experiences ‘oncogenic stress’, which evokes a counter-response to eliminate such hazardous cells. [...] Key Result Similar checkpoint responses were induced in cultured cells upon expression of different oncogenes that deregulate DNA replication. Together with genetic analyses, including a genome-wide assessment of allelic imbalances, our data indicate that early in tumorigenesis (before genomic instability and malignant conversion), human cells activate an…Expand
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References

SHOWING 1-10 OF 56 REFERENCES
Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions
TLDR
It is proposed that, from its earliest stages, cancer development is associated with DNA replication stress, which leads to DNA double-strand breaks, genomic instability and selective pressure for p53 mutations. Expand
c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability.
TLDR
It is proposed that oncogene activation can induce DNA damage and override damage controls, thereby accelerating tumor progression via genetic instability. Expand
A DNA damage checkpoint response in telomere-initiated senescence
TLDR
It is proposed that telomere-initiated senescence reflects a DNA damage checkpoint response that is activated with a direct contribution from dysfunctional telomeres. Expand
53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancer
TLDR
The constitutive activation of the DNA damage checkpoint pathway may be linked to the high frequency of p53 mutations in human cancer, as p53 is a downstream target of Chk2 and ATM. Expand
Rapid destruction of human Cdc25A in response to DNA damage.
TLDR
These results identify specific degradation of Cdc25A as part of the DNA damage checkpoint mechanism and suggest how CDC25A overexpression in human cancers might contribute to tumorigenesis. Expand
DNA Damage Foci at Dysfunctional Telomeres
TLDR
The cellular response to telomere dysfunction is governed by proteins that also control the DNA damage response, and induction of TIFs through TRF2 inhibition provides an opportunity to study theDNA damage response within the context of well-defined, physically marked lesions. Expand
Distinct spatiotemporal dynamics of mammalian checkpoint regulators induced by DNA damage
TLDR
A dynamic nature of Nbs1 interaction with DSB lesions is unraveled and Chk2 is identified as a candidate transmitter of the checkpoint signal, allowing for a coordinated pan-nuclear response to focal DNA damage. Expand
Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status.
TLDR
Hypoxia is an example of a "nongenotoxic" stress which induces p53 activity by a different pathway than DNA-damaging agents, and cells expressing the human papillomavirus E6 gene, which show increased degradation of p53 by ubiquitination and fail to accumulate p53 in response to DNA-damage agents, do increase their p53 levels following heat and hypoxia. Expand
ATM and related protein kinases: safeguarding genome integrity
  • Y. Shiloh
  • Biology, Medicine
  • Nature Reviews Cancer
  • 2003
TLDR
Understanding ATM's mode of action provides new insights into the association between defective responses to DNA damage and cancer, and brings us closer to resolving the issue of cancer predisposition in some A-T carriers. Expand
ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses
TLDR
It is demonstrated that ATR/ATM-dependent phosphorylation of hRad17 is a critical early event during checkpoint signalling in DNA-damaged cells. Expand
...
1
2
3
4
5
...