Promyelocytic leukemia protein
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Promyelocytic leukemia protein (PML) (also known as MYL, RNF71, PP8675 or TRIM19) is the protein product of the PML gene. PML protein is a tumor suppressor
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
required for the assembly of a number of nuclear structures, called PML-nuclear bodies, which form amongst the
chromatin Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...
of the cell nucleus. These
nuclear bodies Nuclear bodies (also known as nuclear domains, or nuclear dots) are membraneless structures found in the cell nuclei of eukaryotic cells. Nuclear bodies include Cajal bodies, the nucleolus, and promyelocytic leukemia protein (PML) nuclear bodies ...
are present in mammalian nuclei, at about 1 to 30 per cell nucleus. PML-NBs are known to have a number of regulatory cellular functions, including involvement in
programmed cell death Programmed cell death (PCD; sometimes referred to as cellular suicide) is the death of a cell as a result of events inside of a cell, such as apoptosis or autophagy. PCD is carried out in a biological process, which usually confers advantage durin ...
, genome stability, antiviral effects and controlling
cell division Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...
. PML mutation or loss, and the subsequent dysregulation of these processes, has been implicated in a variety of cancers.


History

PML was poorly understood until described in the findings of Grignani ''et al'' in their 1996 study of patients with acute promyelocytic leukemia (APL). It was found that the karyotype of 90% of APL patients included a reciprocal translocation, resulting in the fusion of the Retinoic Acid Receptor (RARalpha) gene of chromosome 17 and the PML gene of chromosome 15, which had not previously been characterized. The resultant PML/RARalpha oncofusion gene was shown to disturb normal PML and RARalpha function, thus inhibiting the terminal differentiation of blood precursor cells and allowing the maintenance of a reserve of undifferentiated cells for cancerous progression. This implication of the PML gene in a pathological context led to a greater focus on the gene in future years.


Structure

The PML gene is roughly 53 kilobase pairs in length and is located on the q arm of chromosome 15. It consists of 10 exons that are subject to shuffling through
alternative splicing Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...
, yielding more than 15 known PML
protein isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
s. While the isoforms vary at their
c-terminal domain The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
, they all contain a TRIpartite motif encoded by the first three exons of the gene. The TRIpartite motif consists of a zinc
RING finger The ring finger, third finger, fourth finger, leech finger, or annulary is the fourth digit of the human hand, located between the middle finger and the little finger. Sometimes the term ring finger only refers to the fourth digit of a left-han ...
, two zinc binding domains, termed the B1 and B2 boxes, and an RBCC
dimer Dimer may refer to: * Dimer (chemistry), a chemical structure formed from two similar sub-units ** Protein dimer, a protein quaternary structure ** d-dimer * Dimer model, an item in statistical mechanics, based on ''domino tiling'' * Julius Dimer ...
ization domain composed of two
alpha helical The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...
coiled coil domains. The PML gene is under transcriptional, translational and post translational control. The promoter region of the gene contains targets of Signal Transducer and Activator of Transcription (STATs),
interferon regulatory factors Interferon regulatory factors (IRF) are proteins which regulate transcription of interferons (see regulation of gene expression). Interferon regulatory factors contain a conserved N-terminal region of about 120 amino acids, which folds into a st ...
, and p53 protein, indicating the intricacy of its involvement in cellular functions. In addition to regulation through alternative splicing, the protein product is subject to
post-translational modification Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosome ...
s such as acetylation and phosphorylation. The
c-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
contains serine residues that are
phosphorylated In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...
by casein kinases, and there are several tyrosine and threonine residues which can also be phosphorylation targets. PML phosphorylation triggers further modification through the attachment of
SUMO is a form of competitive full-contact wrestling where a ''rikishi'' (wrestler) attempts to force his opponent out of a circular ring (''dohyō'') or into touching the ground with any body part other than the soles of his feet (usually by thr ...
proteins to the
RING domain In molecular biology, a RING (short for Really Interesting New Gene) finger domain is a protein structural domain of zinc finger type which contains a C3HC4 amino acid motif which binds two zinc cations (seven cysteines and one histidine arranged ...
by
UBC9 SUMO-conjugating enzyme UBC9 is an enzyme that in humans is encoded by the ''UBE2I'' gene. It is also sometimes referred to as "ubiquitin conjugating enzyme E2I" or "ubiquitin carrier protein 9", even though these names do not accurately describe ...
SUMO-conjugating enzyme, which occurs in a cell cycle dependent way. PML contains a SUMO-binding domain necessary for its interaction with other SUMOylated proteins such as itself and many others. Both
ubiquitination Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
and
SUMOylation In molecular biology, SUMO (Small Ubiquitin-like Modifier) proteins are 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 (sometimes w ...
of PML protein can trigger its degradation in the
proteasome Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by w ...
, thus providing a means of modulating PML protein lability within the cell. PML is translated in the cytoplasm of the cell, but its
N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
contains a
nuclear localization signal A nuclear localization signal ''or'' sequence (NLS) is an amino acid sequence that 'tags' a protein for import into the cell nucleus by nuclear transport. Typically, this signal consists of one or more short sequences of positively charged lysines o ...
which causes its import to the nucleus. Within the nucleus, sumoylated PML proteins multimerize with one another through interactions at the RBCC domain. This forms a ring-like structure that binds to the nuclear matrix, forming a PML-Nuclear body (PML-NB). The edge of the ring-like protein multimer features protein threads that extend out from the ring and make contact with chromatin fibers. This maintains the position of the PML-NBs within the nucleus, as well as the stability of the protein. When the chromatin is stressed, such as during apoptosis, the PML-NB becomes unstable and the PML bodies are redistributed into microstructures. These microstructures contain PML protein but not the many interacting proteins normally associated with PML-NBs. PML-NBs are not randomly distributed throughout the nucleus, but are found within the nucleus and are commonly associated with other nuclear bodies such as splicing speckles and
nucleoli The nucleolus (, plural: nucleoli ) is the largest structure in the nucleus of eukaryotic cells. It is best known as the site of ribosome biogenesis, which is the synthesis of ribosomes. The nucleolus also participates in the formation of s ...
, as well as regions that are rich in genes and are actively being transcribed . Particularly, PML-NB have been shown to associate with genes such as the
MHC I MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules (the other being MHC class II) and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on pla ...
cluster of genes, as well as the p53 gene. The exact significance of this association is unclear, however evidence suggests that PML-NBs may influence transcription at these specific gene sites.


Function

The PML-NBs have a wide array of functions, and a large role in cell regulation. They exert their wide range of actions through interactions with varying proteins localized to the PML-NBs. It is thought that the specific biochemical function performed by PML-NBs may be serving as an E3
ligase In biochemistry, a ligase is an enzyme that can catalyze the joining (ligation) of two large molecules by forming a new chemical bond. This is typically via hydrolysis of a small pendant chemical group on one of the larger molecules or the enzym ...
for the sumoylation of other proteins. The true function, however, remains unclear, and several possible models have been proposed for PML-NB function, including nuclear storage of proteins, serving as a dock where other proteins accumulate to be post-translationally modified, direct involvement with transcription, and chromatin regulation. PML-NBs also play a role in
transcriptional regulation In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from alt ...
. PML-NBs have been shown to increase the transcription of some genes, while repressing the transcription of other genes. It has been suggested that the mechanism by which PML-NBs do this is via a chromatin-remodelling processes, although this is uncertain. Due to this apparent contradiction, it is possible that PML-NBs may be heterogeneous structures that have different functions based on their location within the nucleus, the proteins they interact with in a specific area of the nucleus, or the specific PML protein isoforms of which they are composed. In addition to this regulation of transcription, observations of PML-NBs have strongly suggested that the protein complex plays a role in mediating DNA-damage responses. For example, the number and size of PML-NBs increases as the activities of DNA damage sensors ATM and
ATR ATR may refer to: Medicine * Acute transfusion reaction * Ataxia telangiectasia and Rad3 related, a protein involved in DNA damage repair Science and mathematics * Advanced Test Reactor, nuclear research reactor at the Idaho National Laboratory, ...
increase. The nuclear bodies localize to the site of DNA damage, where proteins associated with the repair of DNA and halting of the cell cycle then co-localize. The functional purpose of the interaction between PML-NBs and DNA repair mechanisms remains unclear, but it seems unlikely that they have a role in repairing the DNA directly, due to the co-localization of DNA repair proteins and PML-NBs some time after the DNA has been damaged. Rather, it is thought that PML-NBs may regulate responses to DNA damage by acting as a storage site for proteins involved in DNA repair, regulating the repair directly, or mediating between DNA repair and checkpoint responses. However, it is clear that PML-NBs play a role in mediating checkpoint responses, particularly in causing apoptosis. PML plays an important role in both
p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
dependent and p53-independent apoptotic pathways. PML activates p53 by recruiting the protein to a PML-NBs site and promoting its activation, while inhibiting regulators of the protein such as MDM2 or HAUSP. In pathways that do not use p53 in inducing apoptosis, PML have been shown to interact with CHK2 and induce it to autophosphorylate to become active. In addition to those two apoptotic pathways, Fas-induced apoptosis relies on the PML-NBs to release FLICE-Associated huge protein, which then localizes to the mitochondria to promote the activation of
Caspase-8 Caspase-8 is a caspase protein, encoded by the ''CASP8'' gene. It most likely acts upon caspase-3. ''CASP8'' orthologs have been identified in numerous mammals for which complete genome data are available. These unique orthologs are also presen ...
. Beyond apoptosis, other studies have implicated PML-NBs in cellular
senescence Senescence () or biological aging is the gradual deterioration of functional characteristics in living organisms. The word ''senescence'' can refer to either cellular senescence or to senescence of the whole organism. Organismal senescence inv ...
, particularly its induction. It has been shown to be involved with the formation of certain chromatin features of cells experiencing senescence, such as senescence-associated heterochromatin foci (SAHFs), which are believed to suppress the expression of growth-promoting factors and genes. The formation of these features is the result of histone chaperones, HIRA and ASF1, whose
chromatin remodeling Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out ...
activities here are mediated by the PML-NBs. HIRA localizes to PML-NBs before any other interaction occurs with the DNA.


Role in cancer

Loss of function mutations of the PML protein, particularly resulting from the fusion of the PML gene with RARα gene in Acute promyelocytic leukemias, is implicated in several tumor suppressing apoptotic pathways, particularly those that rely on p53 as noted above. Thus, the loss of PML function confers a cellular survival and proliferation advantage, impedes cellular senescence through loss of SAHFs, and puts a block on cellular differentiation. Both humans and mice have been found to demonstrate an increased propensity for tumor formation upon loss of PML function. PML disruption occurs in a wide variety of cancer types, and results in more metastatic tumors, and correspondingly poorer prognoses. It is thought that, beyond the importance it plays in apoptotic roles, PML inactivation may cause cells to favor tumor progression by allowing the cell to accumulate additional genetic damage. Many proteins involved in genomic stability maintenance rely on the PML-NBs for targeting, and PML loss thus leads to a decrease in repair efficiency within the cell.


Cell cycle role

PML-NB distribution and concentration changes as the cell moves through the
cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
. In G0 phase, few sumoylated PML-NBs are present, but their numbers increase as the cell progresses through G1 to S to G2 stages. During the chromatin condensation occurring during mitosis, the desumoylation of PML causes the dissociation of many associated factors, and the PML proteins self aggregate to form a few, large, aggregates termed mitotic accumulations of PML proteins (MAPPs). In addition to changes in numbers, PML-NBs also associate with different proteins over the lifetime of the cycle, and undergo significant biochemical changes in composition. During the S phase of the cell cycle, PML-NB complexes break apart as their chromatin scaffold changes during replication. The physical breaking of the PML-NBs into smaller fragments promotes the creation of more PML-NBs that exist in G2, however, the expression levels of the PML protein hasn't increased. It is thought that this may serve to preserve the orientation of the chromatids with which the PML-NBs are associated, or monitor the integrity of replication forks.


Antiviral functions

Transcription of PML is increased by the presence of interferon α/β and γ. It is thought that the increased numbers of PML-NBs that result from this increase in expression of the PML protein may result in the sequestering of viral proteins in the PML-NBs. Thus, the virus is unable to make use of them. The proteins held by PML-NBs are then sumoylated, inactivating the virions permanently.


Interactions

Promyelocytic leukemia protein has been shown to
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ANKRD2 Ankyrin Repeat, PEST sequence and Proline-rich region (ARPP), also known as Ankyrin repeat domain-containing protein 2 is a protein that in humans is encoded by the ''ANKRD2'' gene. ARPP is a member of the muscle ankyrin repeat proteins (MARP), wh ...
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CREB-binding protein Cyclic adenosine monophosphate Response Element Binding protein Binding Protein (CREB-binding protein), also known as CREBBP or CBP or KAT3A, is a coactivator encoded by the ''CREBBP'' gene in humans, located on chromosome 16p13.3. CBP has intrin ...
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Cyclin T1 Cyclin-T1 is a protein that in humans is encoded by the ''CCNT1'' gene. Function The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance thro ...
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Death associated protein 6 Death-associated protein 6 also known as Daxx is a protein that in humans is encoded by the ''DAXX'' gene. Function Daxx, a Death domain-associated protein, was first discovered through its cytoplasmic interaction with the classical death rece ...
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GATA2 GATA2 or GATA-binding factor 2 is a transcription factor, i.e. a nuclear protein which regulates the expression of genes. It regulates many genes that are critical for the embryonic development, self-renewal, maintenance, and functionality of bl ...
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HDAC1 Histone deacetylase 1 (HDAC1) is an enzyme that in humans is encoded by the ''HDAC1'' gene. Function Histone acetylation and deacetylation, catalyzed by multisubunit complexes, play a key role in the regulation of eukaryotic gene expression. T ...
, * HDAC3, *
HHEX Hematopoietically-expressed homeobox protein HHEX is a protein that in humans is encoded by the ''HHEX'' gene and also known as Proline Rich Homeodomain protein PRH. This gene encodes a member of the homeobox family of transcription factors, many ...
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MAPK11 Mitogen-activated protein kinase 11 is an enzyme that in humans is encoded by the ''MAPK11'' gene. Function The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical ...
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Nerve Growth factor IB The nuclear receptor 4A1 (NR4A1 for "nuclear receptor subfamily 4 group A member 1") also known as Nur77, TR3, and NGFI-B is a protein that in humans is encoded by the ''NR4A1'' gene. Nuclear receptor 4A1 (NR4A1) is a member of the ''NR4A'' nucle ...
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Nuclear receptor co-repressor 1 The nuclear receptor co-repressor 1 also known as thyroid-hormone- and retinoic-acid-receptor-associated co-repressor 1 (TRAC-1) is a protein that in humans is encoded by the ''NCOR1'' gene. NCOR1 is a transcriptional coregulatory protein which c ...
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Nuclear receptor co-repressor 2 The nuclear receptor co-repressor 2 () is a transcriptional coregulatory protein that contains several nuclear receptor-interacting domains. In addition, NCOR2 appears to recruit histone deacetylases to DNA promoter regions. Hence NCOR2 assists ...
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P53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
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RPL11 60S ribosomal protein L11 is a protein that in humans is encoded by the ''RPL11'' gene. Function Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits a ...
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Retinoblastoma protein The retinoblastoma protein (protein name abbreviated pRb; gene name abbreviated ''Rb'', ''RB'' or ''RB1'') is a proto-oncogenic tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive ...
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Retinoic acid receptor alpha Retinoic acid receptor alpha (RAR-α), also known as NR1B1 (nuclear receptor subfamily 1, group B, member 1) is a nuclear receptor that in humans is encoded by the ''RARA'' gene. NR1B1 is a gene with a protein product and has a chromosomal locat ...
, * SIN3A, *
SKI protein The SKI protein is a nuclear proto-oncogene that is associated with tumors at high cellular concentrations. SKI has been shown to interfere with normal cellular functioning by both directly impeding expression of certain genes inside the nucleus ...
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STAT3 Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family. Function STAT3 is a member of the STAT protein family. In respons ...
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Serum response factor Serum response factor, also known as SRF, is a transcription factor protein. Function Serum response factor is a member of the MADS (MCM1, Agamous, Deficiens, and SRF) box superfamily of transcription factors. This protein binds to the serum ...
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Small ubiquitin-related modifier 1 Small ubiquitin-related modifier 1 is a protein that in humans is encoded by the ''SUMO1'' gene. Function This gene encodes a protein that is a member of the SUMO (small ubiquitin-like modifier) protein family. It is a ubiquitin-like protein an ...
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Sp1 transcription factor Transcription factor Sp1, also known as specificity protein 1* is a protein that in humans is encoded by the SP1 gene. Function The protein encoded by this gene is a zinc finger transcription factor that binds to GC-rich motifs of many promote ...
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TOPBP1 DNA topoisomerase 2-binding protein 1 (TOPBP1) is a scaffold protein that in humans is encoded by the ''TOPBP1'' gene. TOPBP1 was first identified as a protein binding partner of DNA topoisomerase-IIβ by a yeast 2-hybrid screen, giving it its ...
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Thymine-DNA glycosylase G/T mismatch-specific thymine DNA glycosylase is an enzyme that in humans is encoded by the TDG gene. Several bacterial proteins have strong sequence homology with this protein. Function The protein encoded by this gene belongs to the TDG/mug D ...
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Zinc finger and BTB domain-containing protein 16 Zinc finger and BTB domain-containing protein 16 is a protein that in humans is encoded by the ''ZBTB16'' gene. Function This gene is a member of the Krueppel C2H2-type zinc-finger protein family and encodes a zinc finger transcription factor ...
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PER2 PER2 is a protein in mammals encoded by the ''PER2'' gene. ''PER2'' is noted for its major role in circadian rhythms. Discovery The ''per ''gene'' ''was first discovered using forward genetics in '' Drosophilla melanogaster'' in 1971. Mammalia ...
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BMAL1 Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL) or brain and muscle ARNT-Like 1 (BMAL1) is a protein that in humans is encoded by the gene on chromosome 11, region p15.3. It's also known as ''BMAL1'', ''MOP3'', and, less com ...
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CLOCK A clock or a timepiece is a device used to measure and indicate time. The clock is one of the oldest human inventions, meeting the need to measure intervals of time shorter than the natural units such as the day, the lunar month and the ...
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See also

*
RING finger domain In molecular biology, a RING (short for Really Interesting New Gene) finger domain is a protein structural domain of zinc finger type which contains a C3HC4 amino acid motif which binds two zinc cations (seven cysteines and one histidine arrange ...


References


Further reading

* * * * * * *


External links

* {{PDB Gallery, geneid=5371 RING finger proteins