scholarly journals The Mechanism of Radiosensitization by YM155, a Novel Small Molecule Inhibitor of Survivin Expression, is Associated with DNA Damage Repair

2015 ◽  
Vol 37 (3) ◽  
pp. 1219-1230 ◽  
Author(s):  
Songliu Hu ◽  
Songbin Fu ◽  
Xiangying Xu ◽  
Lin Chen ◽  
Jianyu Xu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Small Molecule ◽  
Cellular Localization ◽  
Survivin Expression ◽  
Strand Break ◽  
Double Strand Break ◽  
Double Strand Break Repair ◽  
Dna Double Strand Break ◽  
Molecule Inhibitor ◽  
Break Repair

Background/Aims: Survivin, a member of the inhibitor of apoptosis protein family, is an attractive target for cancer therapy. We investigated the effects of YM155, a small molecule inhibitor of survivin expression, on the radiosensitivity of human non-small cell lung cancer (NSCLC) cell lines and elucidated a relationship between the cellular localization of survivin and DNA double-strand break repair. Methods: The cellular distribution of survivin was determined by Western blotting of subcellular fractions and by immunofluorescent staining in A549 NSCLC cells. Radiation-induced DNA damage was evaluated based on histone H2AX phosphorylation and foci formation. The relationship between the cellular localization of survivin and DNA double-strand break repair was analyzed by Western blotting and co-immunoprecipitations. Results: YM155 down-regulated survivin expression in NSCLC cells in a concentration- and time-dependent manner. An in vitro clonogenic survival assay revealed that YM155 increased the sensitivity of NSCLC cells to radiation. After irradiation, we observed a rapid accumulation of survivin in the nucleus. An immunofluorescent analysis of histone γ-H2AX demonstrated that the inhibition of survivin expression by YM155 resulted in impaired DNA double-strand break repair. Co-immunoprecipitation assays using nuclear extracts revealed an interaction between survivin, Ku70, γ-H2AX, and DNA-PKcs. Furthermore, S2056 autophosphorylation of DNA-PKcs was reduced in survivin-depleted cells. Conclusions: These results suggested that YM155 sensitized NSCLC cells to radiation, at least in part by inhibiting DNA repair and enhancing apoptosis via the down-regulation of survivin expression. YM155 pretreatment inhibited DNA-PKcs autophosphorylation at S2056. Nuclear survivin was involved in DNA double-strand break repair via interactions with members of the DNA double-strand break repair machinery.

scholarly journals Epigenetic Mechanisms in DNA Double Strand Break Repair: A Clinical Review

2021 ◽  
Vol 8 ◽  
Author(s):  
Alejandra Fernandez ◽  
Connor O’Leary ◽  
Kenneth J O’Byrne ◽  
Joshua Burgess ◽  
Derek J Richard ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chromatin Structure ◽  
Dna Methyltransferase ◽  
Strand Break ◽  
Dna Methyltransferases ◽  
Double Strand Break ◽  
Double Strand Break Repair ◽  
Epigenetic Mechanisms ◽  
Dna Double Strand Break ◽  
Break Repair

Upon the induction of DNA damage, the chromatin structure unwinds to allow access to enzymes to catalyse the repair. The regulation of the winding and unwinding of chromatin occurs via epigenetic modifications, which can alter gene expression without changing the DNA sequence. Epigenetic mechanisms such as histone acetylation and DNA methylation are known to be reversible and have been indicated to play different roles in the repair of DNA. More importantly, the inhibition of such mechanisms has been reported to play a role in the repair of double strand breaks, the most detrimental type of DNA damage. This occurs by manipulating the chromatin structure and the expression of essential proteins that are critical for homologous recombination and non-homologous end joining repair pathways. Inhibitors of histone deacetylases and DNA methyltransferases have demonstrated efficacy in the clinic and represent a promising approach for cancer therapy. The aims of this review are to summarise the role of histone deacetylase and DNA methyltransferase inhibitors involved in DNA double strand break repair and explore their current and future independent use in combination with other DNA repair inhibitors or pre-existing therapies in the clinic.

scholarly journals p53 isoform Δ113p53/Δ133p53 promotes DNA double-strand break repair to protect cell from death and senescence in response to DNA damage

Cell Research ◽  
2015 ◽  
Vol 25 (3) ◽  
pp. 351-369 ◽  
Author(s):  
Lu Gong ◽  
Hongjian Gong ◽  
Xiao Pan ◽  
Changqing Chang ◽  
Zhao Ou ◽  
...  
Keyword(s):  
Dna Damage ◽  
Strand Break ◽  
Double Strand Break ◽  
Double Strand Break Repair ◽  
Dna Double Strand Break ◽  
Break Repair

scholarly journals The Caenorhabditis elegans Homolog of Gen1/Yen1 Resolvases Links DNA Damage Signaling to DNA Double-Strand Break Repair

PLoS Genetics ◽  
2010 ◽  
Vol 6 (7) ◽  
pp. e1001025 ◽  
Author(s):  
Aymeric P. Bailly ◽  
Alasdair Freeman ◽  
Julie Hall ◽  
Anne-Cécile Déclais ◽  
Arno Alpi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Caenorhabditis Elegans ◽  
Strand Break ◽  
Double Strand Break ◽  
Double Strand Break Repair ◽  
Dna Damage Signaling ◽  
Dna Double Strand Break ◽  
Break Repair
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