Journal ArticleDOI
DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis
Jirina Bartkova,Zuzana Horejsi,Karen Koed,Alwin Krämer,Frederic Tort,Karsten Zieger,Per Guldberg,Maxwell Sehested,Jahn M. Nesland,Claudia Lukas,Torben F. Ørntoft,Jiri Lukas,Jiri Bartek +12 more
TLDR
It is shown that in clinical specimens from different stages of human tumours of the urinary bladder, breast, lung and colon, the early precursor lesions commonly express markers of an activated DNA damage response.Abstract:
During the evolution of cancer, the incipient tumour experiences 'oncogenic stress', which evokes a counter-response to eliminate such hazardous cells. However, the nature of this stress remains elusive, as does the inducible anti-cancer barrier that elicits growth arrest or cell death. Here we show that in clinical specimens from different stages of human tumours of the urinary bladder, breast, lung and colon, the early precursor lesions (but not normal tissues) commonly express markers of an activated DNA damage response. These include phosphorylated kinases ATM and Chk2, and phosphorylated histone H2AX and p53. 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 ATR/ATM-regulated DNA damage response network that delays or prevents cancer. Mutations compromising this checkpoint, including defects in the ATM-Chk2-p53 pathway, might allow cell proliferation, survival, increased genomic instability and tumour progression.read more
Citations
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Glioma stem cells promote radioresistance by preferential activation of the DNA damage response
Shideng Bao,Qiulian Wu,Roger E. McLendon,Yueling Hao,Qing Ming Shi,Anita B. Hjelmeland,Mark W. Dewhirst,Darell D. Bigner,Jeremy N. Rich +8 more
TL;DR: This work shows that cancer stem cells contribute to glioma radioresistance through preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity, and suggests that CD133-positive tumour cells could be the source of tumour recurrence after radiation.
Journal ArticleDOI
The DNA-damage response in human biology and disease
Stephen P. Jackson,Jiri Bartek +1 more
TL;DR: The authors' improving understanding of DNA-damage responses is providing new avenues for disease management, and these responses are biologically significant because they prevent diverse human diseases.
Journal ArticleDOI
Cancer Metastasis: Building a Framework
Gaorav P. Gupta,Joan Massagué +1 more
TL;DR: Understanding of the origins and nature of cancer metastasis and the selection of traits that are advantageous to cancer cells is promoted.
Journal ArticleDOI
Cellular senescence: when bad things happen to good cells
TL;DR: Understanding the causes and consequences of cellular senescence has provided novel insights into how cells react to stress, especially genotoxic stress, and how this cellular response can affect complex organismal processes such as the development of cancer and ageing.
Journal ArticleDOI
Cell cycle, CDKs and cancer: a changing paradigm
TL;DR: Genetic evidence suggests that tumour cells may also require specific interphase CDKs for proliferation, and selective CDK inhibition may provide therapeutic benefit against certain human neoplasias.
References
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TL;DR: There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels, and recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.
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DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
TL;DR: It is shown that ATM is held inactive in unirradiated cells as a dimer or higher-order multimer, with the kinase domain bound to a region surrounding serine 1981 that is contained within the previously described ‘FAT’ domain.