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30-422: 5111 18538 ENSG00000132646 ENSMUSG00000027342 P12004 P17918 NM_182649 NM_002592 NM_011045 NP_002583 NP_872590 NP_035175 Proliferating cell nuclear antigen ( PCNA ) is a DNA clamp that acts as a processivity factor for DNA polymerase δ in eukaryotic cells and is essential for replication. PCNA is a homotrimer and achieves its processivity by encircling

60-475: A family of small proteins that are covalently attached to and detached from other proteins in cells to modify their function. This process is called SUMOylation (pronounced soo-muh-lā-shun and sometimes written sumoylation ). SUMOylation is a post-translational modification involved in various cellular processes, such as nuclear - cytosolic transport, transcriptional regulation, apoptosis , protein stability, response to stress, and progression through

90-531: A C-terminal peptide is cleaved from the SUMO precursor by a protease (in human these are the SENP proteases or Ulp1 in yeast) to reveal a di-glycine motif. The obtained SUMO then becomes bound to an E1 enzyme (SUMO Activating Enzyme (SAE)) which is a heterodimer (subunits SAE1 and SAE2 ). It is then passed to an E2, which is a conjugating enzyme (Ubc9). Finally, one of a small number of E3 ligating proteins attaches it to

120-588: A DNA helicase called Srs2, which has a role in disrupting Rad51 nucleoprotein filaments fundamental for initiation of homologous recombination. PCNA interacts with many proteins. PCNA has been shown to interact with: Proteins interacting with PCNA via APIM include human AlkB homologue 2, TFIIS-L, TFII-I, Rad51B, XPA, ZRANB3, and FBH1. Antibodies against proliferating cell nuclear antigen (PCNA) or monoclonal antibody termed Ki-67 can be used for grading of different neoplasms , e.g. astrocytoma . They can be of diagnostic and prognostic value. Imaging of

150-446: A number of different outcomes including altered localization and binding partners. The SUMO-1 modification of RanGAP1 (the first identified SUMO substrate) leads to its trafficking from cytosol to nuclear pore complex. The SUMO modification of ninein leads to its movement from the centrosome to the nucleus . In many cases, SUMO modification of transcriptional regulators correlates with inhibition of transcription. One can refer to

180-525: A result, SUMO-4 isn't processed and conjugated under normal conditions, but is used for modification of proteins under stress-conditions like starvation. During mitosis, SUMO-2/3 localize to centromeres and condensed chromosomes, whereas SUMO-1 localizes to the mitotic spindle and spindle midzone, indicating that SUMO paralogs regulate distinct mitotic processes in mammalian cells. One of the major SUMO conjugation products associated with mitotic chromosomes arose from SUMO-2/3 conjugation of topoisomerase II, which

210-421: A role in the major DNA repair pathways of base excision repair , nucleotide excision repair , non-homologous end joining and homologous recombinational repair. SUMOylation also facilitates error prone translation synthesis. SUMO proteins are small; most are around 100 amino acids in length and 12 kDa in mass . The exact length and mass varies between SUMO family members and depends on which organism

240-774: Is a potential therapeutic target in cancer therapy. In 2023 City of Hope National Medical Center published preclinical research on a targeted chemotherapy using AOH1996 that appears to suppress tumor growth without causing discernable side effects. DNA clamp Too Many Requests If you report this error to the Wikimedia System Administrators, please include the details below. Request from 172.68.168.132 via cp1112 cp1112, Varnish XID 945994365 Upstream caches: cp1112 int Error: 429, Too Many Requests at Thu, 28 Nov 2024 08:33:10 GMT Small ubiquitin-like modifier In molecular biology , SUMO ( S mall U biquitin-like Mo difier) proteins are

270-490: Is involved in resynthesis of excised damaged DNA strands during DNA repair , PCNA is important for both DNA synthesis and DNA repair. PCNA is also involved in the DNA damage tolerance pathway known as post-replication repair (PRR). In PRR, there are two sub-pathways: (1) a translesion synthesis pathway, which is carried out by specialised DNA polymerases that are able to incorporate damaged DNA bases into their active sites (unlike

300-479: Is modified exclusively by SUMO-2/3 during mitosis. SUMO-2/3 modifications seem to be involved specifically in the stress response. SUMO-1 and SUMO-2/3 can form mixed chains, however, because SUMO-1 does not contain the internal SUMO consensus sites found in SUMO-2/3, it is thought to terminate these poly-SUMO chains. Serine 2 of SUMO-1 is phosphorylated, raising the concept of a 'modified modifier'. Cellular DNA

330-539: Is produced when the last four amino acids of the C-terminus have been cleaved off to allow formation of an isopeptide bond between the C-terminal glycine residue of SUMO and an acceptor lysine on the target protein. SUMO family members often have dissimilar names; the SUMO homologue in yeast , for example, is called SMT3 (suppressor of mif two 3). Several pseudogenes have been reported for SUMO genes in

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360-446: Is regularly exposed to DNA damaging agents. A DNA damage response (DDR) that is well regulated and intricate is usually employed to deal with the potential deleterious effects of the damage. When DNA damage occurs, SUMO protein has been shown to act as a molecular glue to facilitate the assembly of large protein complexes in repair foci. Also, SUMOylation can alter a protein's biochemical activities and interactions. SUMOylation plays

390-446: Is the lysine conjugated to SUMO, x is any amino acid (aa), D or E is an acidic residue. Substrate specificity appears to be derived directly from Ubc9 and the respective substrate motif. Currently available prediction programs are: SUMO attachment to its target is similar to that of ubiquitin (as it is for the other ubiquitin-like proteins such as NEDD 8). The SUMO precursor has some extra amino acids that need to be removed, therefore

420-482: The GeneRIFs of the SUMO proteins, e.g. human SUMO-1, to find out more. There are 4 confirmed SUMO isoforms in humans; SUMO-1 , SUMO-2 , SUMO-3 and SUMO-4 . At the amino acid level, SUMO1 is about 50% identical to SUMO2. SUMO-2/3 show a high degree of similarity to each other and are distinct from SUMO-1. SUMO-4 shows similarity to SUMO-2/3 but differs in having a Proline instead of Glutamine at position 90. As

450-434: The cell cycle . In human proteins, there are over 53,000 SUMO binding sites, making it a substantial component of fundamental biology. SUMO proteins are similar to ubiquitin and are considered members of the ubiquitin-like protein family. SUMOylation is directed by an enzymatic cascade analogous to that involved in ubiquitination. In contrast to ubiquitin, SUMO is not used to tag proteins for degradation . Mature SUMO

480-492: The cell cycle . Part of the protein was sequenced and that sequence was used to allow isolation of a cDNA clone. PCNA helps hold DNA polymerase delta ( Pol δ ) to DNA. PCNA is clamped to DNA through the action of replication factor C (RFC), which is a heteropentameric member of the AAA+ class of ATPases. Expression of PCNA is under the control of E2F transcription factor -containing complexes. Since DNA polymerase epsilon

510-405: The human genome . SUMO modification of proteins has many functions. Among the most frequent and best studied are protein stability, nuclear - cytosolic transport, and transcriptional regulation. Typically, only a small fraction of a given protein is SUMOylated and this modification is rapidly reversed by the action of deSUMOylating enzymes. SUMOylation of target proteins has been shown to cause

540-502: The DNA, where it acts as a scaffold to recruit proteins involved in DNA replication, DNA repair, chromatin remodeling and epigenetics . Many proteins interact with PCNA via the two known PCNA-interacting motifs PCNA-interacting peptide (PIP) box and AlkB homologue 2 PCNA interacting motif (APIM). Proteins binding to PCNA via the PIP-box are mainly involved in DNA replication whereas proteins binding to PCNA via APIM are mainly important in

570-742: The E3 ligases). SUMOylation is reversible and is removed from targets by specific SUMO proteases. In budding yeast, the Ulp1 SUMO protease is found bound at the nuclear pore, whereas Ulp2 is nucleoplasmic. The distinct subnuclear localisation of deSUMOylating enzymes is conserved in higher eukaryotes. SUMO can be removed from its substrate, which is called deSUMOylation. Specific proteases mediate this procedure (SENP in human or Ulp1 and Ulp2 in yeast). Recombinant proteins expressed in E. coli may fail to fold properly, instead forming aggregates and precipitating as inclusion bodies . This insolubility may be due to

600-515: The Smc5/6 complex) and Pias-gamma and HECT proteins. On Chromosome 17 of the human genome, SUMO2 is near SUMO1+E1/E2 and SUMO2+E1/E2, among various others. Some E3's, such as RanBP2, however, are neither. Recent evidence has shown that PIAS-gamma is required for the SUMOylation of the transcription factor yy1 but it is independent of the zinc-RING finger (identified as the functional domain of

630-482: The context of genotoxic stress. The protein encoded by this gene is found in the nucleus and is a cofactor of DNA polymerase delta. The encoded protein acts as a homotrimer and helps increase the processivity of leading strand synthesis during DNA replication. In response to DNA damage, this protein is ubiquitinated and is involved in the RAD6-dependent DNA repair pathway. Two transcript variants encoding

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660-419: The need for transfection and bypass the problem of difficult to transfect and/or short lived cells, cell permeable replication and/or repair markers can be used. These peptides offer the distinct advantage that they can be used in situ in living tissue and even distinguish cells undergoing replication from cells undergoing repair. caPCNA, a post-translationally modified isoform of PCNA common in cancer cells,

690-446: The normal replicative polymerase, which stall), and hence bypass the damage, and (2) a proposed "template switch" pathway that is thought to involve damage bypass by recruitment of the homologous recombination machinery. PCNA is pivotal to the activation of these pathways and the choice as to which pathway is utilised by the cell. PCNA becomes post-translationally modified by ubiquitin . Mono-ubiquitin of lysine number 164 on PCNA activates

720-413: The nuclear distribution of PCNA (via antibody labeling) can be used to distinguish between early, mid and late S phase of the cell cycle. However, an important limitation of antibodies is that cells need to be fixed leading to potential artifacts. On the other hand, the study of the dynamics of replication and repair in living cells can be done by introducing translational fusions of PCNA. To eliminate

750-408: The presence of codons read inefficiently by E. coli , differences in eukaryotic and prokaryotic ribosomes, or lack of appropriate molecular chaperones for proper protein folding. In order to purify such proteins it may be necessary to fuse the protein of interest with a solubility tag such as SUMO or MBP ( maltose-binding protein ) to increase the protein's solubility. SUMO can later be cleaved from

780-400: The protein comes from. Although SUMO has very little sequence identity with ubiquitin (less than 20%) at the amino acid level, it has a nearly identical structural fold. SUMO protein has a unique N-terminal extension of 10-25 amino acids which other ubiquitin-like proteins do not have. This N-terminal is found related to the formation of SUMO chains. The structure of human SUMO1 is depicted on

810-566: The protein. In budding yeast, there are four SUMO E3 proteins, Cst9, Mms21, Siz1 and Siz2 . While in ubiquitination an E3 is essential to add ubiquitin to its target, evidence suggests that the E2 is sufficient in SUMOylation as long as the consensus sequence is present. It is thought that the E3 ligase promotes the efficiency of SUMOylation and in some cases has been shown to direct SUMO conjugation onto non-consensus motifs. E3 enzymes can be largely classed into PIAS proteins, such as Mms21 (a member of

840-415: The right. It shows SUMO1 as a globular protein with both ends of the amino acid chain (shown in red and blue) sticking out of the protein's centre. The spherical core consists of an alpha helix and a beta sheet . The diagrams shown are based on an NMR analysis of the protein in solution. Most SUMO-modified proteins contain the tetrapeptide consensus motif Ψ-K-x-D/E where Ψ is a hydrophobic residue, K

870-447: The same protein have been found for this gene. Pseudogenes of this gene have been described on chromosome 4 and on the X chromosome. PCNA is also found in archaea, as a processivity factor of polD , the single multi-functional DNA polymerase in this domain of life. PCNA was originally identified as an antigen that is expressed in the nuclei of cells during the DNA synthesis phase of

900-413: The translesion synthesis pathway. Extension of this mono-ubiquitin by a non-canonical lysine-63-linked poly-ubiquitin chain on PCNA is thought to activate the template switch pathway. Furthermore, sumoylation (by small ubiquitin-like modifier , SUMO) of PCNA lysine-164 (and to a lesser extent, lysine-127) inhibits the template switch pathway. This antagonistic effect occurs because sumoylated PCNA recruits

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