ReviewChromatin-remodelling mechanisms in cancer
Section snippets
Epigenetics and cancer
Epigenetics refers to modifications in genome function that occur without changes in DNA. Eu- or heterochromatic organizations, once established can be somatically maintained as heritable epigenetic states [1], [2]. Chromatin conformation depends on several epigenetic processes acting in concert, such as DNA methylation, histone-tail acetylation, poly-ADP-ribosylation and ATP-dependent chromatin-remodelling mechanisms (i.e. SWI/SNF, ISWI). Distinct histone covalent modifications on a specific
DNA methylation
DNA methylation is a chemical heritable modification characterized by the covalent addition of a methyl group to cytosines. In human somatic cells, DNA methylation typically occurs at CpG dinucleotides, which accounts for ∼1% of the total genome [15]. Moreover, 60–90% of all disperse CpG sequences are methylated. On the other hand, CpG islands (GC-rich regions located at the 5′ ends in ∼60% of human genes) possess high relative densities of unmethylated CpG dinucleotides at all stages of
Histone acetylation
Histone acetylation is the most frequent post-translational histone modification, consisting on the addition of acetyl groups to lysines mostly from the amino-terminal tails of core histones (Fig. 3) [87]. More recently, it has been demonstrated acetylation at the histone core domains, which can be involved in the recruitment of ATP-dependent chromatin-remodelling complexes [88], [89]. The acetylation pattern depends on the activity of histone acetyltransferases (HATs) and histone deacetylases
Poly-ADP-ribosylation
NAD+ can be hydrolyzed by various enzymatic activities, such as PARPs, MARTs, SIRTs and ADP-ribosyl cyclases, which release nicotinamide (Nam) from NAD+ to produce poly-ADP-ribose, mono-ADP-ribosyl-protein, acetyl-ADP-ribose or cyclic-ADP-ribose, respectively (Fig. 4). An ADP-ribosylation reaction involves the cleavage of NAD+ in nicotinamide and ADP-ribose. Poly-ADP-ribosylation (PARlation) generates a homopolymer of ADP-ribose units called poly-ADP-ribose (PAR) that are catalyzed by
ATP-dependent chromatin-remodelling mechanisms
Chromatin structure can be modified locally by chromatin-remodelling complexes, which transiently dislocate DNA/nucleosome interactions by utilizing the energy of ATP hydrolysis to reposition nucleosomes, modulating accessibility of specific genes to the transcriptional machinery. Chromatin-remodelling complexes are also involved in other processes that require alteration of chromatin structure including DNA repair, DNA synthesis, mitosis and genomic stability. Because of this, ATP-dependent
Epigenetic biomarkers in cancer
DNA methylation constitutes a valuable marker not only for cancer detection but also for prognosis. It has been suggested that the circulating DNA in serum or plasma could be used in the detection of silent tumours through the analysis of patterns of hypermethylated islands, which can be tumour specific. DNA methylation is stable and can be studied by PCR. The pattern of methylation of specific genes may be a molecular marker in thyroid, breast, prostate, gastric and colon carcinomas [224]. A
Concluding remarks
Considerable information has accumulated indicating that aberrant epigenetic gene regulation collaborates with genetic alterations in cancer development [39], [84]. Some epigenetic alterations during cancer development may include: (1) DNA hypermethylation of regulatory sequences of DNA repair enzyme genes, tumour-suppressor genes, hormone receptors, or invasion-metastasis inhibitors; (2) global DNA hypomethylation linked to genomic instability and the activation of metastasis-related genes;
Acknowledgements
We are indebted to the PDT Program (Project 91/29) from the National Council of Science and Technology from Uruguay, the PEDECIBA Program from the University of the Republic (Uruguay) and Mary Curie Fellowship from the European Community.
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