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Regulation of cell differentiation by the DNA damage response. Trends Cell Biol

Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
Trends in cell biology (Impact Factor: 12.31). 02/2011; 21(5):312-9. DOI: 10.1016/j.tcb.2011.01.004
Source: PubMed

ABSTRACT When faced with DNA double-strand breaks (DSBs), vertebrate cells activate DNA damage response (DDR) programs that preserve genome integrity and suppress malignant transformation. Three established outcomes of the DDR include transient cell cycle arrest coupled with DNA repair, apoptosis, or senescence. However, recent studies in normal and cancer precursor or stem cells suggest that a fourth potential outcome, cell differentiation, is under the influence of DDR programs. Here we review and discuss the emerging evidence that supports the linkage of signaling from DSBs to the regulation of differentiation, including some of the molecular mechanisms driving this under-appreciated DDR outcome. We also consider the physiologic and pathologic consequences of defects in DDR signaling on cell differentiation and malignant transformation.

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    • "The relationship between the radioresistance, cell differentiation and chromatin structure is not yet fully understood. Contrary to the granulocyte differentiation, the DSB repair activity was shown to be up-regulated during the early adipogenesis, due to an upregulation of DNA-PK expression (Meulle et al., 2008) Thus, recent reports suggest ambiguous and bidirectional dependence between the DSB repair and differentiation (Sherman et al., 2011). Though heterochromatinization associated with cell differentiation can be suspected of complicating or even precluding DSB repair (as discussed in ''Results and Discussion'', and in our earlier works, Falk et al., 2007, 2010; Lukasova et al., 2013), the situation with mature granulocytes might be exceptional because of their unique function closely connected with the specific chromatin structure. "
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    • "An appealing hypothesis is that this strategy could have a broader effect on gene expression and cell differentiation programs. A growing body of data from the last ten years implicates the DDR in regulating precursor or stem cell differentiation programs (Sherman et al., 2011). One clear example is the development of vertebrate adaptive immune systems that requires the programmed induction and subsequent repair of DSBs during antigen receptor gene rearrangements to assemble a complete Ig gene via V(D)J recombination. "
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    ABSTRACT: It is well-known that DNA-damaging agents induce genome instability, but only recently have we begun to appreciate that chromosomes are fragile per se and frequently subject to DNA breakage. DNA replication further magnifies such fragility, because it leads to accumulation of single-stranded DNA. Recent findings suggest that chromosome fragility is similarly increased during transcription. Transcripts produced by RNA polymerase II (RNAPII) are subject to multiple processing steps, including maturation of 5' and 3' ends and splicing, followed by transport to the cytoplasm. RNA maturation starts on nascent transcripts and is mediated by a number of diverse proteins and ribonucleoprotein particles some of which are recruited cotranscriptionally through interactions with the carboxy-terminal domain of RNAPII. This coupling is thought to maximize efficiency of pre-mRNA maturation and directly impacts the choice of alternative splice sites. Mounting evidence suggests that lack of coordination among different RNA maturation steps, by perturbing the interaction of nascent transcripts with the DNA template, has deleterious effects on genome stability. Thus, in the absence of proper surveillance mechanisms, transcription could be a major source of DNA damage in cancer. Recent high-throughput screenings in human cells and budding yeast have identified several factors implicated in RNA metabolism that are targets of DNA damage checkpoint kinases: ATM (ataxia telangiectasia mutated) and ATR (ATM-Rad3 related) (Tel1 and Mec1 in budding yeast, respectively). Moreover, inactivation of various RNA processing factors induces accumulation of γH2AX foci, an early sign of DNA damage. Thus, a complex network is emerging that links DNA repair and RNA metabolism. In this review we provide a comprehensive overview of the role played by pre-mRNA processing factors in the cell response to DNA damage and in the maintenance of genome stability.
    Frontiers in Genetics 06/2013; 4:102. DOI:10.3389/fgene.2013.00102
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    • "The relationship between the radioresistance, cell differentiation and chromatin structure is not yet fully understood. Contrary to the granulocyte differentiation, the DSB repair activity was shown to be up-regulated during the early adipogenesis, due to an upregulation of DNA-PK expression (Meulle et al., 2008) Thus, recent reports suggest ambiguous and bidirectional dependence between the DSB repair and differentiation (Sherman et al., 2011). Though heterochromatinization associated with cell differentiation can be suspected of complicating or even precluding DSB repair (as discussed in ''Results and Discussion'', and in our earlier works, Falk et al., 2007, 2010; Lukasova et al., 2013), the situation with mature granulocytes might be exceptional because of their unique function closely connected with the specific chromatin structure. "
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    ABSTRACT: Cell differentiation is associated with extensive gene silencing, heterochromatinization and potentially decreasing need for repairing DNA double-strand breaks (DSBs). Differentiation stages of blood cells thus represent an excellent model to study DSB induction, repair and misrepair in the context of changing higher-order chromatin structure. We show that immature granulocytes form γH2AX and 53BP1 foci, contrary to the mature cells; however, these foci colocalize only rarely and DSB repair is inefficient. Moreover, specific chromatin structure of granulocytes probably influences DSB induction.
    Applied radiation and isotopes: including data, instrumentation and methods for use in agriculture, industry and medicine 01/2013; 83. DOI:10.1016/j.apradiso.2013.01.029 · 1.06 Impact Factor
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