The Export Credit Guarantee Corporation of India (ECGC) has released the ECGC PO Final Result on 2nd November. A total of 77 candidates are selected for ECGC PO (Probationary Officer) post against the total of 75 vacancies advertised. The result has been released in the form of a PDF File where you will find the roll number and registration number of the finally selected candidates. The exam was held on 29th May 2022. Also, note that the list released by the board is provisional.
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At the present time, 18 HDACs have been identified in humans that fall into four classes: class I HDACs (HDAC1, 2, 3 and 8) share sequence similarity with the yeast RPD3 deacetylase, are ubiquitously expressed, and they are localized mainly in the nucleus. Class II HDACs (HDAC4, 5, 6, 7, 9 and 10) are homologous to the yeast Hda1 deacetylase, are nuclear and cytoplasmic, and restricted to certain tissues. Class II HDACs are further subdivided into class IIa (HDAC4, 5, 7 and 9) and class IIb (HDAC6 and 10). Class III HDACs are represented by sirtuins (SIRT1 to SIRT7), a family of seven HDACs sharing homology with yeast silent information regulator 2 (Sir2). Class IV has only one member, HDAC11, which shares conserved residues with both class I and II HDACs [63]. Class I, II, and III HDACs have been implicated in the DNA damage response, homologous recombination (HR), and chromatin integrity. This is explained below, and summarized in Table 1.
Bhaskara et al. [42, 72] showed that HDAC3 is important for DSB repair. HDAC3 associates with nuclear receptor corepressor (NCOR) and silencing mediator for retinoic and thyroid receptor (SMRT) [73], and is considered a locus-specific corepressor that is recruited to promoters to repress genes regulated by nuclear hormone receptors and other transcription factors [74]. Conditional deletion demonstrated the absolute requirement for cell viability of HDAC3 in murine embryonic fibroblasts (MEFs) [72]. The latter MEFs underwent apoptosis due to impaired S phase progression and formation of DSBs, rather than altered transcriptional programs. The DNA damage was blocked when cells were taken out of the cell cycle by serum starvation, suggesting that HDAC3 acted during S phase. In another study [42], HDAC3-null MEFs increased histone acetylation (H3K9, H3K14, H4K5 and H4K12) in late S phase. Knockdown of NCOR1 and SMRT increased acetylated H4K5 and caused DNA damage, indicating that the HDAC3/NCOR/SMRT axis may be critical for maintaining chromatin structure and genomic stability. Furthermore, two studies have linked HDAC3 to maintenance of the mitotic spindle assembly [75, 76]. Ishii et al. [75] reported on the localization of HDAC3 to the mitotic spindle, and showed that HDAC3 knockdown led to chromosome misalignment, impaired kinetochore-microtubule attachment, and mitotic spindle collapse. Eot-Houllier et al. [76] showed that HDAC3 knockdown induced spindle assembly checkpoint activation and sister chromatid dissociation. Further, down-regulation of HDAC3 mimics actions of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat) in reducing replication fork velocity and increasing origin firing at sites of replication, likely due to chromatin changes [77].
Namdar et al. [80] reported that HDAC6 inhibition with tubacin or shRNA activated the intrinsic apoptosis pathway in cancer cells; this led to accumulation of γH2AX, and the expression of growth arrest and DNA damage 153 (GADD153/DDIT3), a transcription factor upregulated in response to cellular stress. Tubacin treatment enhanced cell death induced by topoisomerase II inhibitors etoposide and doxorubicin, and by the pan-HDAC inhibitor SAHA, in transformed cells (LNCaP, MCF-7), an effect not observed in normal cells (human foreskin fibroblast cells). Further, tubacin increased the accumulation of γH2AX and activated Chk2. GADD153/DDIT3 induction was augmented when tubacin was combined with SAHA. The authors suggested that HDAC6-selective inhibition enhances the efficacy of certain anticancer agents in transformed cells [80].
Kaidi et al. [21] have shown that human SIRT6 has a role in promoting DNA end-resection, a crucial step in DSB repair by HR. SIRT6 depletion impaired the accumulation of replication protein A (RPA) and single-stranded DNA at damage sites, reduced the rate of HR, and sensitized cells to DSB-inducing agents. The authors identified CtIP as a SIRT6 interaction partner, and showed that SIRT6-dependent CtIP deacetylation promotes DSB resection. Schwer et al. [101] have shown that SIRT6 deletion causes hyperacetylated histone H3K9 and H3K56, two chromatin marks implicated in the regulation of gene activity and chromatin structure, in various brain regions. McCord et al. [102] observed that SIRT6 forms a complex with DNAPK and promotes DSB repair. In addition, the role of SIRT6 in genomic stability has been demonstrated in aging mouse models [84].
HDAC inhibitors can induce growth arrest of neoplastically-transformed cells and trigger apoptosis via one or more pathways. These events are associated with altered patterns of acetylation in histone and non-histone proteins, including key players involved in the regulation of gene expression, apoptosis, cell cycle progression, redox signaling, mitotic division, DNA repair, cell migration, and angiogenesis [63]. Subsequent to the role of HDACs in maintaining genome stability, as discussed above, histone hyperacetylation induced by HDAC inhibitors causes structural alterations in chromatin. This can open up regions of DNA that are normally protected by heterochromatin, enabling DNA-damaging agents to gain access to the exposed template. Importantly, HDAC inhibitors have been shown to decrease the expression of DNA repair proteins such as Ku70 [108], BRCA1 [109], RAD51 [110] and CtIP [20]. It is not clear whether transcription mediates HDAC inhibitor actions in these circumstances [111], and indeed non-transcriptional targets of HDAC inhibitors have been proposed [112, 113]. Thus, HDAC inhibitors have the potential to target multiple signaling and repair mechanisms in the DNA damage pathway by targeting histones and non-histone proteins, as illustrated in Figure 1.
SFN has been shown to cause both DSBs and single-strand breaks (SSBs) in cancer cells. Sekine-Suzuki et al. [134] observed that 20 μM SFN triggered cell cycle arrest, induced DSB, and elevated γH2AX levels in cervical cancer (HeLa) cells. DSBs generated by SFN were comparable to that triggered with 12 Gy of X-rays. These DSBs were repaired mainly by HR through Rad51 foci formation and not by NHEJ [134]. Sestili et al. [135] reported that a short exposure of cells with SFN (10-30 μM for 1-3 h) triggered SSBs in Jurkat lymphoma and HUVEC cells. They found that DNA damage was causally linked to ROS generation and GSH depletion [135]. DSBs also were triggered in colon cancer cell lines SW620 at 10-50 μM [136] and HCT116 cells at 15 μM SFN, resulting in sustained γH2AX expression (our unpublished data). In prostate cancer cells, SFN-induced DNA damage involved the Chk2-mediated phosphorylation of protein phosphatase Cdc25C [137].
Selenium compounds have been reported to cause DNA damage-mediated apoptosis in cancer cells [183]. Recently, two papers described the mechanisms by which selenium compounds trigger DNA damage-induced cell death in cancer cells but not in normal cells [184, 185]. Qi et al. [184] examined methylseleninic acid (MSA, 0-10 μM), methyl selenocysteine (MSC, 0-500 μM), and sodium selenite (0-20 μM) in mismatch repair (MMR)-deficient HCT116 colorectal cancer cells and MMR-proficient HCT116 cells with MutL homolog 1 (MLH1) complementation. The authors found that compared with MMR-deficient HCT116 cells, HCT116+hMLH1 cells were significantly more sensitive to oxidative DNA lesions and γH2AX induction. Further, response to selenium compounds was dependent on ATM kinase and ROS, and required hMLH1-hPMS2. Addition of the ATM kinase inhibitor KU55933, the antioxidant NAC, or the superoxide dismutase mimic Tempo, suppressed the selenium-induced effects. The authors suggested that the hMLH1-hPMS2 complex senses and processes selenium-induced oxidative DNA damage and transmits the signal to ATM kinase, leading to the activation of G2/M checkpoint and death pathways [184]. Hence, in this case, a DNA repair complex acts via genomic instability and mutation to induce cell death. Wu et al. [185] showed that selenium compounds activated similar responses in normal MRC5 cells; however, rather than apoptosis induction they activated cell senescence, as evidenced by the expression of senescence-associated β-galactosidase and BrdU incorporation. In view of the HDAC inhibition, as noted previously for these compounds, it will be interesting to probe whether histone modifications have a role to play in the observed DNA damage signaling. In this regard, we know that MSA and MSC activate ATM [184], which is known to control the transcription of DNA damage genes in response to HDAC inhibition [186]. SM, another selenium compound, also decreased cell proliferation and induced cell-cycle arrest by increasing GADD34 and GADD153 expression [187]. However, such effects were not seen in mammary and prostate cancer cells [188]. Selenocystine, a nutritionally available selenoamino acid, was shown to induce ROS formation leading to DNA strand breaks in cancer cells, but not in normal human fibroblasts [189]. In fact, in normal fibroblast cells, selenium was identified as an important cofactor for various antioxidant enzymes that enhance DNA repair in cells [190].
In vivo studies with dietary polyphenols have shown encouraging results on DNA damage and tumor inhibition. Tyagi et al [304] showed that resveratrol (50 mg/kg bw) treatment inhibited head and neck squamous cell carcinoma (FaDu) tumor growth in nude mice, and γH2AX and cleaved caspase-3 were strongly increased in xenografts from resveratrol-treated mice compared to controls. Vanhees et al. [305] have shown that prenatal exposure to both genistein and quercetin supplements in mice induced DSBs and DNA rearrangements in the mixed-lineage leukemia (MLL) gene, especially in the presence of compromised DNA repair. Toyoizumi et al. [306] reported that co-administration of isoflavones and NaNO2 caused DNA damage in mouse stomach via the formation of radicals. Amin et al. [307] observed that EGCG, in combination with luteolin, increased apoptosis in head and neck and lung cancer xenografted tumors in nude mice, possibly by ATM-dependent Ser(15) phosphorylation of p53 resulting from DNA damage. 2ff7e9595c
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