The DNA Damage Response: Making It Safe to Play with Knives
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...Notable among the apoptosis-inducing stresses are signaling imbalances resulting from elevated levels of oncogene signaling, as mentioned earlier, and DNA damage associated with hyperproliferation....
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...The telomeres, composed of multiple tandem hexanucleotide repeats, shorten progressively in nonimmortalized cells propagated in culture, eventually losing the ability to protect the ends of chromosomal DNAs from end-to-end fusions; such fusions generate unstable dicentric chromosomes whose resolution results in a scrambling of karyotype that threatens cell viability....
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...Most notable is a DNAdamage sensor that functions via the TP53 tumor suppressor (Junttila and Evan, 2009); TP53 induces apoptosis by upregulating expression of the Noxa and Puma BH3-only proteins, doing so in response to substantial levels of DNA breaks and other chromosomal abnormalities....
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...Because heritable phenotypes, e.g., inactivation of tumor suppressor genes, can also be acquired through epigenetic mechanisms such asDNAmethylation and histonemodifications (Berdasco and Esteller, 2010; Esteller, 2007; Jones and Baylin, 2007), some clonal expansions may well be triggered by nonmutational changes affecting the regulation of gene expression....
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...The eventual immortalization of rare variant cells that proceed to form tumors has been attributed to their ability to maintain telomeric DNA at lengths sufficient to avoid triggering senescence or apoptosis, achieved most commonly by upregulating expression of telomerase or, less frequently, via an alternative recombination-based telomere maintenance mechanism....
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...Different classes of proteins are implicated in DDR, among which the sensors specifically recognize the lesions to DNA, whereas the mediators and the effectors transduce the signal from the nucleus to the cytosol where several processes are contextually activated in order to better face up to adverse conditions.(102,103) For instance, cell cycle checkpoints are soon activated to block proliferation until lesions are repaired....
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1,363 citations
Cites background from "The DNA Damage Response: Making It ..."
...The initial recruitment and activation of ATM at sites of damage are followed by modifications of the surrounding chromatin—phosphorylation of H2AX—which in turns facilitates the recruitment of ubiquitin ligases that modify chromatin to assemble multiprotein complexes (33)....
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References
5,132 citations
"The DNA Damage Response: Making It ..." refers background in this paper
...A critical aspect of this process involves the phosphorylation of Ser139 on the specialized histone H2AX called gH2AX (Figure 1A) (Rogakou et al., 1998)....
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4,871 citations
"The DNA Damage Response: Making It ..." refers background in this paper
...Indeed, BRCA2, BACH1, and PALB2 mutations predispose carriers to breast cancer formation when monoallelic and lead to FA syndrome—complementation groups D1, J, and N, respectively—when biallelic....
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...Alternatively, assembly of RAD51 filaments on RPA-coated ssDNA mediated by BRCA2 can lead to HR (Figure 2B) (West, ouble-Strand Breaks 2003)....
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...Depletion of HSCs has been observed in a variety of mouse models defective for DDR components, including ATM, BRCA2, ERCC1, FANCC, Ku80, LIG4, MSH2, XPD, and mouse telomerase RNA (mTR) (Niedernhofer, 2008; Park and Gerson, 2005; Sharpless and DePinho, 2007)....
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...Heterozygous individuals carrying mutations of the BRCA1 or BRCA2 genes have a 40%–80% risk of developing breast cancer (Fackenthal and Olopade, 2007)....
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...Moreover, PARP1 inhibitors have been successfully used to treat tumors that carry mutations in HR genes, such as BRCA1 and BRCA2 (Jackson and Bartek, 2009)....
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"The DNA Damage Response: Making It ..." refers background in this paper
...These include the determination to undergo apoptosis or enter terminal differentiation through senescence, the activation of heightened immune surveillance, DNA damage prophylaxis through tanning, as well as DNA repair itself (Cui et al., 2007; Gasser and Raulet, 2006; Zhou and Elledge, 2000)....
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...Localization of DDR factors to sites of DNAdamage is initiated by sensor proteins that directly recognize specific DNA lesions and activate the DDR (Zhou and Elledge, 2000)....
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...Following the recognition of DNA lesions by sensor proteins, ATM and ATR initially phosphorylate mediator proteins, which can amplify the DDR by acting as recruiters of ATM/ATR substrates (Zhou and Elledge, 2000)....
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...The most extensively studied component of this response is p53, which is regulated by ATM and CHK2 in response to DSBs (Figure 1A) (Zhou and Elledge, 2000). p53 induces cell-cycle arrest, apoptosis, or senescence in response to DNA damage by transcriptionally regulating, among others, the CDK…...
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2,967 citations
"The DNA Damage Response: Making It ..." refers background in this paper
...A large number of DDR-deficient mice and various human DDR syndromes, such as A-T, BS, and FA, display aberrant meiotic progression and infertility (Table 2) (Biton et al., 2008; Bohr, 2008; Matzuk and Lamb, 2008)....
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