The impact of chromatin in human cancer: Linking DNA methylation to gene silencing

ArticleinCarcinogenesis 23(7):1103-9 · August 2002with9 Reads
DOI: 10.1093/carcin/23.7.1103 · Source: PubMed
Abstract
For decades, chromatin was considered to be an inert structure whose only role was the compacting and confining of DNA inside the eukaryotic nucleus. However, tremendous progress in this field over the last 10 years has dramatically elevated chromatin to a key position in the control of gene activity. Its role in mediating the transformation of a normal cell into a malignant state is particularly interesting. On one side of this story there is the discovery that aberrant methylation patterns in an increasing number of tumour suppressor and DNA repair genes determine carcinogenetic transformation; while on the other side, there is the existence of a series of methyl-DNA binding activities that recruit co-repressor complexes and modify the structure of the chromatin to produce a transcriptionally silenced state. Although this field has seen rapid progress in recent years, detailed mechanisms by which this machinery modifies chromatin structure to its appropriate state and the specific targeting of repressor complexes have yet to be resolved. In this review we present the models of how repressor complexes may modify chromatin structure and mediate silencing of tumour suppressor and DNA repair genes.
    • "Such an event can ultimately prevent the initiation of transcription and make it difficult for TBP and other enzymes, including transcription factors to function properly on TATA box sequences, leading to transcription blocking [69]. The slower rate of repair and generation of DSBs in CpG island sequence can have a twofold effect, while slow repair ensures less production of potentially lethal DSBs, concurrently this process can affect important functions like DNA methylation and transcriptional silencing, and thus offering a scope of future study in relation to oncogenesis [70]. "
    [Show abstract] [Hide abstract] ABSTRACT: Sequences like the core element of TATA box and CpG island are frequently encountered in the genome and related to transcription. The fate of repair of clustered abasic sites in such sequences of genomic importance is largely unknown. This prompted us to investigate the sequence dependence of cleavage efficiency of APE1 enzyme at abasic sites within the core sequences of TATA box and CpG island using fluorescence dynamics and reaction kinetics. Simultaneous molecular dynamics study through steady state and time resolved fluorescence spectroscopy using unique ethidium bromide dye release assay confirmed an elevated amount of abasic site cleavage of the TATA box sequence as compared to the core CpG island. Reaction kinetics showed that catalytic efficiency of APE1 for abasic site cleavage of core CpG island sequence was ∼4 times lower as compared to that of the TATA box. Higher value of Km was obtained from the core CpG island sequence than the TATA box sequence. This suggests a greater binding effect of APE1 enzyme on TATA sequence that signifies a prominent role of the sequence context of the DNA substrate. Evidently, a faster response from APE1 was obtained for clustered abasic damage repair of TATA box core sequences than CpG island consensus sequences. The neighboring bases of the abasic sites in the complementary DNA strand were found to have significant contribution in addition to the flanking bases in modulating APE1 activity. The repair refractivity of the bistranded clustered abasic sites arise from the slow processing of the second abasic site, consequently resulting in decreased overall production of potentially lethal double strand breaks. Copyright © 2014 Elsevier B.V. All rights reserved.
    Full-text · Article · Jun 2014
    • "Związek metylacji DNA i modyfikacji histonów nie jest do końca poznany. Niemniej w układzie tym istotną rolę odgrywają białka wiążące się do metylowanych sekwencji CpG (MBP, ang metyl-CpG binding proteins), jak i same metylotransferazy DNA, które mogą przyłączać deacetylazy histonowe (HDAC) oraz białka remodelujące chromatynę [2,3]. Wyniki wielu badań wskazują, że mechanizmy związane z epigenetyczną kontrolą ekspresji genów odgrywają istotną rolę w patogenezie nowotworów. "
    Full-text · Dataset · Apr 2014 · PLoS ONE
    • "knock down decreases HDAC1 binding to the RGS10 promoter in chemoresistant ovarian cancer cells HDAC1 and DNMT1 contribute to gene silencing through recruiting transcriptional repressors to promoter regions333435 and work together to suppress gene expression [24,36]. Our data suggest that HDAC and DNMT activities cooperatively silence RGS10 (Fig. 4C). "
    [Show abstract] [Hide abstract] ABSTRACT: RGS10 is an important regulator of cell survival and chemoresistance in ovarian cancer. We recently showed that RGS10 transcript expression is suppressed during acquired chemoresistance in ovarian cancer. The suppression of RGS10 is due to DNA hypermethylation and histone deacetylation, two important mechanisms that contribute to silencing of tumor suppressor genes during cancer progression. Here, we fully investigate the molecular mechanisms of epigenetic silencing of RGS10 expression in chemoresistant A2780-AD ovarian cancer cells. We identify two important epigenetic regulators, HDAC1 and DNMT1, that exhibit aberrant association with RGS10 promoters in chemoresistant ovarian cancer cells. Knockdown of HDAC1 or DNMT1 expression, and pharmacological inhibition of DNMT or HDAC enzymatic activity, significantly increases RGS10 expression and cisplatin-mediated cell death. Finally, DNMT1 knock down also decreases HDAC1 binding to the RGS10 promoter in chemoresistant cells, suggesting HDAC1 recruitment to RGS10 promoters requires DNMT1 activity. Our results suggest that HDAC1 and DNMT1 contribute to the suppression of RGS10 during acquired chemoresistance and support inhibition of HDAC1 and DNMT1 as an adjuvant therapeutic approach to overcome ovarian cancer chemoresistance.
    Full-text · Article · Jan 2014
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