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Journal ArticleDOI

Genome instability: a mechanistic view of its causes and consequences

01 Mar 2008-Nature Reviews Genetics (Nature Publishing Group)-Vol. 9, Iss: 3, pp 204-217
TL;DR: The causes and consequences of instability are reviewed with the aim of providing a mechanistic perspective on the origin of genomic instability.
Abstract: Genomic instability in the form of mutations and chromosome rearrangements is usually associated with pathological disorders, and yet it is also crucial for evolution. Two types of elements have a key role in instability leading to rearrangements: those that act in trans to prevent instability--among them are replication, repair and S-phase checkpoint factors--and those that act in cis--chromosomal hotspots of instability such as fragile sites and highly transcribed DNA sequences. Taking these elements as a guide, we review the causes and consequences of instability with the aim of providing a mechanistic perspective on the origin of genomic instability.
Citations
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Journal ArticleDOI
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.
Abstract: Tumour-associated cell cycle defects are often mediated by alterations in cyclin-dependent kinase (CDK) activity. Misregulated CDKs induce unscheduled proliferation as well as genomic and chromosomal instability. According to current models, mammalian CDKs are essential for driving each cell cycle phase, so therapeutic strategies that block CDK activity are unlikely to selectively target tumour cells. However, recent genetic evidence has revealed that, whereas CDK1 is required for the cell cycle, interphase CDKs are only essential for proliferation of specialized cells. Emerging evidence suggests that tumour cells may also require specific interphase CDKs for proliferation. Thus, selective CDK inhibition may provide therapeutic benefit against certain human neoplasias.

3,146 citations


Cites background from "Genome instability: a mechanistic v..."

  • ...In addition, cells are exposed to exogenous and endogenous insults that can induce small mutations as well as gross chromosomal rearrangement...

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Journal ArticleDOI
24 Jul 2017-Nature
TL;DR: It is reported that cGAS localizes to micronuclei arising from genome instability in a mouse model of monogenic autoinflammation, after exogenous DNA damage and spontaneously in human cancer cells, and it is established that interferon-stimulated gene expression is induced inmicronucleated cells, concluding that micronsuclei represent an important source of immunostimulatory DNA.
Abstract: DNA is strictly compartmentalized within the nucleus to prevent autoimmunity; despite this, cyclic GMP-AMP synthase (cGAS), a cytosolic sensor of double-stranded DNA, is activated in autoinflammatory disorders and by DNA damage. Precisely how cellular DNA gains access to the cytoplasm remains to be determined. Here, we report that cGAS localizes to micronuclei arising from genome instability in a mouse model of monogenic autoinflammation, after exogenous DNA damage and spontaneously in human cancer cells. Such micronuclei occur after mis-segregation of DNA during cell division and consist of chromatin surrounded by its own nuclear membrane. Breakdown of the micronuclear envelope, a process associated with chromothripsis, leads to rapid accumulation of cGAS, providing a mechanism by which self-DNA becomes exposed to the cytosol. cGAS is activated by chromatin, and consistent with a mitotic origin, micronuclei formation and the proinflammatory response following DNA damage are cell-cycle dependent. By combining live-cell laser microdissection with single cell transcriptomics, we establish that interferon-stimulated gene expression is induced in micronucleated cells. We therefore conclude that micronuclei represent an important source of immunostimulatory DNA. As micronuclei formed from lagging chromosomes also activate this pathway, recognition of micronuclei by cGAS may act as a cell-intrinsic immune surveillance mechanism that detects a range of neoplasia-inducing processes.

934 citations

Journal ArticleDOI
TL;DR: The diverse mechanisms that lead to DNA-damage generation and the activation of DNA- damage-response signalling pathways are discussed, together with the evidence for their contribution to the establishment and maintenance of cellular senescence in the context of organismal ageing and cancer development.
Abstract: Cellular senescence is associated with ageing and cancer in vivo and has a proven tumour-suppressive function. Common to both ageing and cancer is the generation of DNA damage and the engagement of the DNA-damage response pathways. In this Review, the diverse mechanisms that lead to DNA-damage generation and the activation of DNA-damage-response signalling pathways are discussed, together with the evidence for their contribution to the establishment and maintenance of cellular senescence in the context of organismal ageing and cancer development.

866 citations


Additional excerpts

  • ...The observation of a selective pressure in somatic cells for the inactivation of DDR genes during cancer progression is consistent with known cancer predisposition in patients and mouse models that carry germline mutations which impair DDR gene function...

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Journal ArticleDOI
TL;DR: The factors and cellular processes that control R loop formation and the mechanisms by which R loops may influence gene expression and the integrity of the genome are discussed.

825 citations


Cites background from "Genome instability: a mechanistic v..."

  • ...Yeast THO and THSC/TREX-2 R loop-forming mutants show a transcription-associated hyperrecombination phenotype and elevated chromosome and plasmid loss (reviewed in Aguilera and Gómez-González, 2008)....

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  • ...Similarly, DNA repeats with the potential to form hairpins are a strong source of DNA breaks and DNA polymerase stalling (reviewed in Aguilera and Gómez-González, 2008; Mirkin and Mirkin, 2007; Pearson et al., 2005)....

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Journal ArticleDOI
TL;DR: These mechanisms ensure that the local DNA damage response, which enables replication fork progression and DNA repair in S phase, is coupled with cell cycle transitions.
Abstract: Aberrant DNA replication is a major source of the mutations and chromosome rearrangements that are associated with pathological disorders. When replication is compromised, DNA becomes more prone to breakage. Secondary structures, highly transcribed DNA sequences and damaged DNA stall replication forks, which then require checkpoint factors and specialized enzymatic activities for their stabilization and subsequent advance. These mechanisms ensure that the local DNA damage response, which enables replication fork progression and DNA repair in S phase, is coupled with cell cycle transitions. The mechanisms that operate in eukaryotic cells to promote replication fork integrity and coordinate replication with other aspects of chromosome maintenance are becoming clear.

760 citations


Cites background from "Genome instability: a mechanistic v..."

  • ...Genetic mutations that affect enzymes involved in replication result in an accumulation of DNA intermediates that trigger recombination and genome instabilit...

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References
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Book
01 Jan 2006
TL;DR: Nucleotide excision repair in mammalian cells: genes and proteins Mismatch repair The SOS response and recombinational repair in prokaryotes Mutagenesis in proKaryote Mutagenisation in eukaryotes Other DNA damage tolerance responses in eUKaryotes.
Abstract: DNA damage Mutations The reversal of base damage Base excision repair Nucleotide excision repair in prokaryotes Nucleotide excision repair in lower eukaryotes Nucleotide excision repair in mammalian cells: general considerations and chromatin dynamics Nucleotide excision repair in mammalian cells: genes and proteins Mismatch repair The SOS response and recombinational repair in prokaryotes Mutagenesis in prokaryotes Mutagenesis in eukaryotes Other DNA damage tolerance responses in eukaryotes Hereditary diseases with defective responses to DNA damage

5,297 citations

Journal ArticleDOI
22 Apr 1993-Nature
TL;DR: The spontaneous decay of DNA is likely to be a major factor in mutagenesis, carcinogenesis and ageing, and also sets limits for the recovery of DNA fragments from fossils.
Abstract: Although DNA is the carrier of genetic information, it has limited chemical stability. Hydrolysis, oxidation and nonenzymatic methylation of DNA occur at significant rates in vivo, and are counteracted by specific DNA repair processes. The spontaneous decay of DNA is likely to be a major factor in mutagenesis, carcinogenesis and ageing, and also sets limits for the recovery of DNA fragments from fossils.

5,209 citations


"Genome instability: a mechanistic v..." refers background in this paper

  • ...Key to the understanding of TAR and TAM is the fact that ssDNA is chemically more unstable than dsDN...

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Journal ArticleDOI
TL;DR: In this paper, a histone H2AX species that has been phosphorylated specifically at serine 139 was found to be a major component of DNA double-stranded break.

5,132 citations

Journal ArticleDOI
TL;DR: The results clearly establish ATM as the major kinase involved in the phosphorylation of H2AX and suggest that ATM is one of the earliest kinases to be activated in the cellular response to double-strand breaks.

1,909 citations

Journal ArticleDOI
14 Apr 2005-Nature
TL;DR: A panel of human lung hyperplasias, all of which retained wild-type p53 genes and had no signs of gross chromosomal instability, and found signs of a DNA damage response, including histone H2AX and Chk2 phosphorylation, p53 accumulation, focal staining of p53 binding protein 1 (53BP1) and apoptosis as discussed by the authors.
Abstract: DNA damage checkpoint genes, such as p53, are frequently mutated in human cancer, but the selective pressure for their inactivation remains elusive. We analysed a panel of human lung hyperplasias, all of which retained wild-type p53 genes and had no signs of gross chromosomal instability, and found signs of a DNA damage response, including histone H2AX and Chk2 phosphorylation, p53 accumulation, focal staining of p53 binding protein 1 (53BP1) and apoptosis. Progression to carcinoma was associated with p53 or 53BP1 inactivation and decreased apoptosis. A DNA damage response was also observed in dysplastic nevi and in human skin xenografts, in which hyperplasia was induced by overexpression of growth factors. Both lung and experimentally-induced skin hyperplasias showed allelic imbalance at loci that are prone to DNA double-strand break formation when DNA replication is compromised (common fragile sites). We propose 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.

1,829 citations