TRF 2 | TTAGGG repeat binding factor 2

Telomeric repeat-binding factor 2 also known as TRF2 is a 500 amino acid containing telomere specific protein. This nuclear protein with a HTH myb-type DNA-binding domain is a component of the telomere nucleoprotein complex. Usually present at telomeres in metaphase of the cell cycle, TRF2 is a second negative regulator of telomere length where it protects against end-to-end fusion of chromosomes by binding to the telomeric double-stranded TTAGGG repeat. Absence of TRF2 leads to damage of telomeres which are now no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. Thus it plays a role in successful progression through the cell division cycle. TRF2 shows ubiquitous expression in most of the tissues with high expression in spleen, thymus, prostate, uterus, testis, small intestine, colon and peripheral blood leukocytes. A component of the shelterin complex (telosome), TRF2 differs from TERF1 in that its N terminus is basic rather than acidic.

TRF 1 | TTAGGG repeat binding factor 1

TRF1 well known as TTAGGG repeat-binding factor 1 or Telomeric repeat-binding factor 1 is a nuclear protein known to bind the telomeric double-stranded TTAGGG repeat and negatively regulate telomere length and protection. This DNA associated regulatory protein contains a HTH myb-type DNA-binding domain and is known to associate with the mitotic spindle and regulate it. A component of the shelterin complex (telosome) composed of TERF1, TERF2, TINF2, TERF2IP ACD and POT1, TERF1 associates with arrays of double-stranded TTAGGG repeats added by telomerase and protects chromosome ends. It has two isoforms of TRF1 and Pin2 of which Pin2 expression is tightly regulated during the cell cycle. TRF1 colocalizes with telomeric DNA in interphase and metaphase cells and is located at chromosome ends during metaphase.

PARP

Poly (ADP-ribose) polymerase or PARP is an enzyme taking active part in several cellular processes which includes mainly DNA repair and programmed cell death. The PARP family of proteins comprises of seventeen members with different structure and function within in the cell. PARPs are known to polymerize ADP-ribose (PAR) from nicotinamide adenine dinucleotide (NAD) that can be degraded by the enzyme PARG (poly (ADP-ribose) glycohydrolase). Moreover PARPs are also involved in base excision repair and thus repair single-stranded DNA nicks. PARPs are also involved in ATP depletion thus leading to lysis and cell death. PARP mediated post-translational modification of proteins such as CTCF affects the amount of DNA methylation at CpG dinucleotides.

PARP 2

Poly [ADP-ribose] polymerase 2 commonly known as PARP2 is a 583 amino acid containing enzyme belonging to the PARP family with a PARP alpha-helical domain and a PARP catalytic domain that catalyzes a poly (ADP-ribosylation) reaction. A component of base excision repair (BER) complex, PARP2, forms homodimer and heterodimer with PARP1. This nuclear protein functions in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosylation) of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This modification follows DNA damages and appears as an obligatory step in detection/signaling pathway thus repairing DNA strand breaks. The basic residues within the N-terminal region of this protein may bear potential DNA-binding properties, and may be involved in the nuclear and/or nucleolar targeting of the protein. It is widely expressed in actively dividing tissues. Two alternatively spliced transcript variants encoding distinct isoforms have been found.

MBD 3 | Methyl-CpG-binding Domain 3

Methyl-CpG-binding domain protein 3 also known as MBD3 is a nuclear protein belonging to the NURD complex family with a MBD (methyl-CpG-binding) domain. This DNA associated, transcription factor is involved in chromatin remodeling and methylates DNA. MBD3 acts as a transcriptional repressor and plays a role in gene silencing.

MBD 1

Methyl-CpG-binding domain protein 1 also known as MBD1 is a transcriptional repressor that binds CpG islands in promoters where the DNA is methylated at position 5 of cytosine within CpG dinucleotides. MBD1 is a nuclear protein belonging to the methyl CPG binding domain family with three CXXC-type zinc fingers and a MBD (methyl-CpG-binding) domain. This intracellular protein is also known to play a prime role in gene silencing by recruiting AFT7IP, which in turn recruits factors such as the histone methyltransferase SETDB1. MBD1 forms a complex with SETDB1 and ATF7IP that represses transcription and couples DNA methylation and histone 'Lys-9' trimethylation. It is widely expressed in most of the tissues and is upregulated by interferons.

HDAC | Histone deacetylase

Histone deacetylases are a class of enzymes that remove acetyl groups from a ε-N-acetyl lysine amino acid on a histone deacetylating the histones and thus increasing the positive charge of histone tails and encouraging high-affinity binding between the histones and DNA backbone. The increased DNA binding condenses DNA structure, preventing transcription. Action of HDAC is opposite to that of histone acetyltransferase. HDAC proteins are found in three groups, the first two groups belong to the classical HDACs and their activities are inhibited by trichostatin A (TSA) whereas the third group is a family of NAD+-dependent proteins not affected by TSA. The class I HDACs, comprises of HDAC 1, 2 and 8 and are primarily found in the nucleus, whereas HDAC 3 is found both in the nucleus, cytoplasm and also membrane associated whereas the Class II HDACs (HDAC 4, 5, 6, 7 9 and 10) are able to shuttle between the nucleus and the cytoplasm depending on different signals.

HDAC 5 | Histone deacetylase 5

HDAC5 also known as Histone deacetylase 5 is an enzyme involved in the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) thus giving a tag for epigenetic repression. HDAC5 plays an important role in transcriptional regulation, cell cycle progression and developmental events. Like other histone deacetylases HDAC5 which belongs to the histone deacetylase family and type 2 subfamily is known to form large multiprotein complexes. It is involved in muscle maturation by repressing transcription of myocyte enhancer MEF2C. This nuclear protein is known to shuttle between the nucleus and the cytoplasm during myocyte differentiation, thus allowing the expression of myocyte enhancer factors. It is ubiquitously expressed in most of the tissues.

HDAC 11 | Histone deacetylase 11

Histone deacetylase 11 or HDAC11 as the name suggests is a histone deacetylase enzyme responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) thus giving a tag for epigenetic repression. A nuclear protein HDAC11 controls DNA expression by modifying the core histone octamers that package DNA into dense chromatin structures and repress gene expression. HDAC11 belongs to the histone deacetylase family and is known to play an important role in transcriptional regulation, cell cycle progression and developmental events and acts via the formation of large multiprotein complexes. Activity of HDAC11 is inhibited by a known histone deacetylase inhibitor, trapoxin. This protein is strongly expressed in brain, heart, skeletal muscle, kidney and testis.

HDAC 10 | Histone deacetylase10

Histone deacetylase 10 or HDAC10 as the name suggests is a histone deacetylase enzyme responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) thus giving a tag for epigenetic repression. HDAC10 belongs to the histone deacetylase family and type 2 subfamily and is known to play an important role in transcriptional regulation, cell cycle progression and developmental events and acts via the formation of large multiprotein complexes. A nuclear protein HDAC10 is however excluded from the nucleoli. This protein is ubiquitously expressed in most of the tissues with high expression in liver, spleen, pancreas and kidney.

Epigenetics

Epigenetics can be defined as any aspect other than DNA sequence that influences the development of an organism. These changes may be phenotypic or genetic caused by mechanisms other than changes in the underlying DNA sequence and may remain throughout the life of an individual and may also be hereditary in nature. These non-genetic factors cause the genes of an individual to behave or express differently. Cellular differentiation is such an example of epigenetic change where during morphogenesis, totipotent stem cells gives rise to various pluripotent cell lines of the embryo which in turn become fully differentiated cells this is because the chromatin proteins associated with DNA may be activated or silenced. This accounts for why the differentiated cells in a multi-cellular organism express only the genes that are necessary for their own activity. Epigenetics has many and varied potential uses in medical applications, modern evolutionary synthesis, genomic imprinting and related disorders, transgenerational epigenetic observations, as well as in cancer and developmental abnormalities.

Epigenetic code

Epigenetic code is a defining code in every eukaryotic cell consisting of the specific epigenetic modification in each cell. Histone modifications defined by the histone code and additional epigenetic modifications such as DNA methylation are a part of the epigenetic code. Acetylation of the N-terminal tail domains of core histones is a well known source of epigenetic information that operate as part of a predictive and heritable epigenetic code that specifies patterns of gene expression through differentiation and development. Moreover the base for the epigenetic code is a system above the genetic code of a single cell. The genetic code in each cell of an individual is the same, but the epigenetic code is tissue and cell specific. The epigenetic code may be read (ie. exert a functional effect) either through non-histone proteins that bind in an acetylation-dependent manner, or through direct effects on chromatin structure.

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HDAC 7 | Histone deacetylase 7

Histone deacetylase 7 is a thymus-specific, intracellular, transcription factor belonging to the class IIa histone deacetylase family. Reports suggest that dephosphorylation and nuclear localization of HDAC7 is promoted by Myosin phosphatase, thus regulating the repression of Nur77 and inhibition of apoptosis in CD4+CD8+ double-positive thymocytes. HDAC7 plays a specific role in maintaining vascular integrity by repressing the expression of matrix metalloproteinase (MMP) 10. It promotes repression mediated by transcriptional co repressor NCOR2 and is an efficient co repressor of the androgen receptor (AR). It is also responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4).

DNMT | DNA Methyl transferase

Common epigenetic modifications found in eukaryotic organisms ranging from fungi to mammals include DNA methylation which is mainly performed by DNA methyltransferase (DNMT). DNMT is an enzyme responsible for generating and maintaining DNA methylation patterns that control different genome functions. DNMT enzymes exhibit distinct biochemical properties and biological functions, due to their structural differences. The highly variable N-terminal extensions of these nuclear proteins harbor various evolutionarily conserved domains and motifs, some of which have been shown to be involved in functional specializations. In prokaryotes, the major role of DNA methylation is to protect host DNA against degradation by restriction enzymes. In eukaryotes, DNA methylation has been implicated in the control of several cellular processes, including differentiation, gene regulation, and embryonic development. Recent findings also suggest an important role of DNMT in oncogenesis and its importance as a candidate target for anticancer therapy.

DNMT 3B | DNA Methyl transferase 3B

DNMT3B well known as DNA (cytosine-5)-methyltransferase 3B is a nuclear protein belonging to the C5-methyltransferase family with an ADD-type zinc finger and a PWWP domain. This DNA associated enzyme is essential for genome wide de novo methylation and is required for development (at least in mouse) and catalytically methylating cytosines in CpG pairs. DNA methylation is coordinated with methylation of histones. Out of the six isoforms reported isoforms 4 and 5 are probably not functional due to the deletion of two conserved methyltransferase motifs. DNMT3B forms a universal repressor complex containing DNMT3B and ZHX1. It interacts with other proteins like HDAC1, HDAC2, HP1 proteins, SUV39H1, and components of the histone methylation system, the ATP-dependent chromatin remodeling enzyme SMARCA5. Ubiquitously expressed in most of the tissues. Defects in DNMT3B are a cause of a rare autosomal recessive disorder immunodeficiency-centromeric instability-facial anomalies syndrome (ICF) biochemically characterized by hypomethylation of CpG sites in some regions of heterochromatin.

NMT 1 | DNA Methyl transferase 1

DNMT1 well known as DNA (cytosine-5)-methyltransferase 1 is a 1616 amino acid containing nuclear protein that methylates CpG residues. DNMT1 belongs to the C5-methyltransferase family with two BAH domains and a CXXC-type zinc finger. It is known to preferentially methylate hemimethylated DNA and is also responsible for maintaining methylation patterns established in development. DNA methylation is coordinated with methylation of histones. Direct interaction between DMAP1, HDAC2 and NMT1 results in the formation of a complex. DNMT1 mediates transcriptional repression by direct binding to HDAC2. Although DNMT1 is known to be ubiquitously expressed in most of the tissues, isoform 2 is less expressed than isoform 1. Moreover its expression is reduced to non detectable levels at the G0 phase of the cell cycle and is dramatically induced upon entrance into the S-phase of the cell cycle.

DNMT3a | DNA Methyl transferase 3a

DNMT3A also known as DNA (cytosine-5)-methyltransferase 3A is a nuclear protein belonging to the C5-methyltransferase family with an ADD-type zinc finger and a PWWP domain. This nuclear protein localizes to euchromatin and is essential for genome wide de novo methylation and is also essential for development. DNA methylation is coordinated with methylation of histones. DNMT3A associates with HDAC1 through its ADD-type zinc-finger. It binds to the ZNF238 transcriptional repressor and is also known to interact with other DNA methyltransferases like DNMT1 and DNMT3B.

DNA topoisomerase I-related function

DNA topoisomerase 1 is a topoisomerase enzyme that catalyzes ATP-independent breakage of single-stranded DNA, followed by passage and rejoining. It catalyzes reaction that leads to the conversion of one topological isomer of DNA to another. Eukaryotic topoisomerase I and II can relax both negative and positive supercoils, whereas prokaryotic enzymes relax only negative supercoils. DNA topoisomerase 1 belongs to the eukaryotic type I topoisomerase family and is a monomer known to interact with SV40 Large T antigen that allows viral DNA replication. It is specifically inhibited by camptothecin (CPT), a plant alkaloid with antitumor activity. It generally has diffuse nuclear localization with some enrichment in nucleoli but on CPT treatment, it is cleared from nucleoli into nucleoplasm. Chromosomal aberration involving DNA topoisomerase 1 is found in a form of therapy-related myelodysplastic syndrome.

ATF 2 | Activating transcription factor 2

ATF2 is a nuclear protein detected abundantly in the brain. ATF2 also known as Cyclic AMP-dependent transcription factor ATF-2 is a transcriptional activator that binds DNA as a dimer and can form a homodimer in the absence of DNA. It binds through its N-terminal region to UTF1 which acts as a co activator of ATF2 transcriptional activity. ATF2 belonging to the bZIP family and ATF subfamily has a bZIP domain and a C2H2-type zinc finger. This transcriptional activator binds to the cAMP-responsive element (CRE) which is a consensus sequence present in many viral and cellular promoters. Interaction with JUN redirects JUN to bind to CRES preferentially over the 12-O-tetradecanoylphorbol-13-acetate response elements (TRES) as part of an ATF2-c-Jun complex.