Dna modifications

presented by HAFIZ M WASEEM
university of education LAHORE Pakistan
i am from mailsi vehari and studied in lahore
bsc in science college multan
msc from lahore

1. HAFIZ M WASEEM UNIVERSITY OF EDUCATION LAHORE

2. ADVANCED MOLECULAR BIOLOGY DNA MODIFICATIONS

3. Epigenetics Epigenetics refers to a variety of processes that have heritable effects on gene expression programs without changes in DNA sequence.

4. Nucleosome and Chromatin Dimers of Histones H2A, H2B, H3, H4 A round which 146 base pairs of DNA are wrapped. H1 linker histone stabilizes the assembly of the octameric core into chromatin-specific higher-order structures. In addition to nucleosomes, the chromatin fiber contains a large variety of additional accessory proteins numerous histone variants that are not randomly distributed in chromatin but are expressed in developmentally restricted and cell type specific patterns. The yeast and mammalian centromeres contain a variant of histone H3, Cse4/CENP-A, that was found to be essential for centromere assembly and function. Likewise, H2A.Z, a variant of histone H2A, is shown to be required for one or more essential roles in chromatin structure that cannot be replaced by bona fide histone H2A.

5. Histones are rich in lysin and Arginine residues The amino-terminal portion of the core histones contains a flexible and highly basic tail region, the target of several types of post-translational modifications.   Crystallographic analysis of the nucleosome has shown that the histone tails are external to the core structure and are therefore accessible for protein-protein interactions

6. Modifications in histone Acetylation- Deactylation Methylation Phosphorylation Two of the covalent modifications affecting the tails, acetylation and phosphorylation, have been shown to be reversible. Consequently, if the presence of a modification influences transcription in a particular way, its removal may have the opposing effect. 

7. Acetylation- Deactylation Acetylation is the one so far more thoroughly analysed [ 21 ]. The histones amino termini lysines undergo acetylation-deacetylation switches depending on the different physiological conditions. The balance between these modifications is achieved through the action of enzymes dubbed histone acetyltransferases (HATs) and histone deacetyltransferases (HDACs). These specific enzymes catalyse the transfer of an acetyl group from acetyl-CoA molecules to the lysine ɛ-amino groups on the N-terminal tails of histones. Acetylation of lysines neutralizes the charge on histones therefore, increasing chromatin accessibility. Following the discovery of histone acetylation, numerous studies have shown that this type of modification occurs throughout the whole eukaryotic genome. 

8. Methylation Methylation has been suggested to be biochemically stable and irreversible. In other words, methylation could be a dead-end modification. Once you have it, there is no way back. The major methylation sites within histone tails are the basic amino acid side chains of lysine and arginine residues). H istone methyltransferases (HMTs) is the enzyme responsible for these modifications.  Several studies on bulk histones have indicated that mammals possess different ratios of methylated species of lysine and arginine, depending on the cell type or tissue source.

9. In vivo, methylated lysines can be found either in a mono-, di-, or trimethylated state, whereas arginines can be either mono- or dimethylated (which can be asymmetric or symmetric) H3 methylation at Lys 9 has the opposite effect and therefore is found in regions where transcription is repressed by chromatin structure

10. Histone Phosphorylation Histone phosphorylation  involves the addition of phosphate groups to the  histone  tail. it is somewhat less well understood than are acetylation and methylation. Several nuclear protein kinases and protein phosphatases are known to add or remove phosphate group to histones.

11. Histone phosphorylation is a critical intermediate step in chromosome condensation during cell division, transcriptional regulation, and DNA damage repair. Unlike acetylation and methylation, histone phosphorylation establishes interactions between other histone modifications and serves as a platform for effector proteins, which leads to a downstream cascade of events. Phosphorylation occurs on all core histones, with differential effects on each. Phosphorylation of histone H3 at serine 10 and 28, and histone H2A on T120, are involved in chromatin compaction and the regulation of chromatin structure and function during mitosis. These are important markers of cell cycle and cell growth that are conserved throughout eukaryotes. Phosphorylation of H2AX at S139 (resulting in γH2AX) serves as a recruiting point for DNA damage repair proteins and is one of the earliest events to occur after DNA double-strand breaks.