HERC2 is a giant
E3 ubiquitin protein ligase, implicated in DNA repair regulation, pigmentation and neurological disorders. It is encoded by a gene of the same name belonging to the HERC family, which typically encodes large protein products with
C-terminal
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 ...
HECT domain
In molecular biology, the HECT domain is a protein domain found in ubiquitin-protein ligases. The name HECT comes from 'Homologous to the E6-AP Carboxyl Terminus'. Proteins containing this domain at the C terminus include ubiquitin-protein ligase ...
s and one or more
RCC1
Regulator of chromosome condensation 1, also known as RCC1, Ran guanine nucleotide exchange factor and RanGEF, is the name for a human gene and protein.
RCC1 also functions as a guanine nucleotide exchange factor for Ran GTPase.
Interactions
R ...
-like (RLD)
domains.
History
HERC2, previously referred to as the ''rjs'' gene locus, was first identified in 1990 as the gene responsible for two
phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
s in mice: the runty, jerky, sterile (rjs) phenotype and the juvenile development and fertility-2 (Jdf2) phenotype. Mutant
allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
s are known to cause hypo-pigmentation and pink eye phenotypes, as well reduced growth, jerky gait, male sterility, female semi-sterility, and maternal behaviour defects in mice.
Gene locus
The full ''HERC2'' gene is located at 15q13, encoded by 93
exon
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...
s and its transcription is under the control of a
CpG rich
promoter. This region on chromosome 15 is susceptible to breaks during chromosomal rearrangement and there are at least 12 partial duplicates of HERC2 between 15q11–15q13.
At least 15 HERC2
SNPs
In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...
have been identified and they are strongly associated with human iris colour variability, functioning to repress expression of
OCA2
P protein, also known as melanocyte-specific transporter protein or pink-eyed dilution protein homolog, is a protein that in humans is encoded by the oculocutaneous albinism II (''OCA2'') gene. The P protein is believed to be an integral membrane ...
's product.
Protein structure
HERC2 encodes a 4834-amino acid protein with a theoretical size of 528 kDa. While a full structure has not yet been elucidated, potentially due to its large size, partial structures of its domains have been captured.
It has an N-terminal bilobed HECT domain, conferring E3 ligase functionality, as well as 3 RLD domains with seven-bladed β-propeller folds. In addition to these HERC family hallmarks, it has several other motifs; a cytochrome-b5-like domain, several potential phosphorylation sites, and a ZZ-type zinc finger motif.
This is likely involved in protein binding, and has recently been identified as a SUMOylation target following DNA damage.
Expression of HERC2 is ubiquitous, though particularly high in the brain and testes. Cellular localisation is predominantly to the nucleus and cytoplasm.
![3KCI The third RLD domain of HERC2](https://upload.wikimedia.org/wikipedia/commons/7/78/3KCI_The_third_RLD_domain_of_HERC2.jpg)
]
![2KEO cytochrome-b5-like domain](https://upload.wikimedia.org/wikipedia/commons/0/00/2KEO_cytochrome-b5-like_domain.jpg)
]
![4L1M Structure of the first RCC1-like domain of HERC2](https://upload.wikimedia.org/wikipedia/commons/9/92/4L1M_Structure_of_the_first_RCC1-like_domain_of_HERC2.jpg)
]
Protein function
Pigmentation
SNPs of HERC2 are strongly associated with
eye color, iris colour variability in humans. In particular, the rs916977 and rs12913832 SNPs have been reported as good predictors of this trait, and the latter is also significantly associated with
skin
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...
and
hair
Hair is a protein filament that grows from follicles found in the dermis. Hair is one of the defining characteristics of mammals.
The human body, apart from areas of glabrous skin, is covered in follicles which produce thick terminal and f ...
colour. The ancestral
allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
is linked to darker pigmentation and dominant over the lighter pigment recessive allele.
The rs12913832 SNP, located in intron 86 of the HERC2 gene contains a silencing sequence that can inhibit the expression of OCA2 and, if both recessive alleles are present, can homozygously cause blue eyes. This
genotype
The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...
is present in almost all people with blue eyes and is hypothesised as being the founder mutation of blue eyes in humans.
[; ; ]
The rs916977 SNP is most common in
Europe
Europe is a large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a Continent#Subcontinents, subcontinent of Eurasia ...
; particularly in the north and east, where it nears fixation. The variant is also found at high frequencies in
North Africa
North Africa, or Northern Africa is a region encompassing the northern portion of the African continent. There is no singularly accepted scope for the region, and it is sometimes defined as stretching from the Atlantic shores of Mauritania in ...
, the
Near East
The ''Near East''; he, המזרח הקרוב; arc, ܕܢܚܐ ܩܪܒ; fa, خاور نزدیک, Xāvar-e nazdik; tr, Yakın Doğu is a geographical term which roughly encompasses a transcontinental region in Western Asia, that was once the hist ...
,
Oceania
Oceania (, , ) is a region, geographical region that includes Australasia, Melanesia, Micronesia, and Polynesia. Spanning the Eastern Hemisphere, Eastern and Western Hemisphere, Western hemispheres, Oceania is estimated to have a land area of ...
and the
Americas
The Americas, which are sometimes collectively called America, are a landmass comprising the totality of North and South America. The Americas make up most of the land in Earth's Western Hemisphere and comprise the New World.
Along with th ...
.
DNA repair pathways
HERC2 is a component of the
replication fork
In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritanc ...
and essential for DNA damage repair pathways. Regulating DNA repair pathways is necessary, as unchecked they can target and excise undamaged DNA, potentially leading to mutation.
It is involved in coordinating the
Chk1
Checkpoint kinase 1, commonly referred to as Chk1, is a serine/threonine-specific protein kinase that, in humans, is encoded by the ''CHEK1'' gene. Chk1 coordinates the DNA damage response (DDR) and cell cycle checkpoint response. Activation of Chk ...
-directed DNA damage/cell cycle checkpoint response by regulating the stability of the deubiquitination enzyme
USP20
Ubiquitin carboxyl-terminal hydrolase 20 is an enzyme that in humans is encoded by the ''USP20'' gene.
Ubiquitin-specific protease 20 (USP20), also known as ubiquitin-binding protein 20 and VHL protein-interacting deubiquitinating enzyme 2 (VDU2), ...
. Under normal conditions HERC2 associates with USP20 and ubiquitinates it for degradation. Under replication stress, for example a
DNA polymerase
A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create ...
mismatch error, USP20 disassociates from HERC2 and deubiquitinates
claspin, stabilising it to then bind and activate Chk1. This allows for DNA replication to be paused and the error corrected.
At the site of doubles stranded breaks, HERC2 facilitates the binding of
RNF8
E3 ubiquitin-protein ligase RNF8 is an enzyme that in humans is encoded by the ''RNF8'' gene. RNF8 has activity both in immune system functions and in DNA repair.
Function
The protein encoded by this gene contains a RING finger motif and an ...
, a RING finger ubiquitin ligase to the E2 ubiquitin-conjugating enzyme UBC13. This association is required for RNF8 mediated Lys-63 poly-ubiquitination signalling, which both recruits and retains repair factors at the site of DNA damage to commence
homologous recombination repair
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may ...
.
HERC2 is also involved in regulating
nucleotide excision repair
Nucleotide excision repair is a DNA repair mechanism. DNA damage occurs constantly because of chemicals (e.g. intercalating agents), radiation and other mutagens. Three excision repair pathways exist to repair single stranded DNA damage: Nucle ...
by ubiquitinating the
XPA
DNA repair protein complementing XP-A cells is a protein that in humans is encoded by the ''XPA'' gene. Function
Nucleotide excision repair (NER) is a major pathway for repairing a variety of bulky DNA damages including those introduced by UV i ...
repair protein for proteolysis. XPA is involved in recognising DNA damage and provides a scaffold for other repair factors to bind at the damage site.
Centrosome assembly
HERC2 has been implicated in regulating stable
centrosome
In cell biology, the centrosome (Latin centrum 'center' + Greek sōma 'body') (archaically cytocentre) is an organelle that serves as the main microtubule organizing center (MTOC) of the animal cell, as well as a regulator of cell-cycle progres ...
architecture in conjunction with NEURL4 other ubiquitinated binding partners. Its absence is associated with aberrant centrosome morphology.
Iron metabolism
HERC2 has recently been associated with regulating iron metabolism through ubiquitinating the F-box and leucine-rich repeat protein 5 (
FBXL5
F-box/LRR-repeat protein 5 is a protein that in humans is encoded by the ''FBXL5'' gene.
This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitu ...
) for proteasomal degradation. FBXL5 regulates the stability of the iron regulatory protein (IR2), which in turn controls the stability of proteins overlooking cellular iron homeostasis. Depletion of HERC2 results in decreased cellular iron levels. Iron is an essential nutrient in cells, but high levels can be cytotoxic, so maintaining cellular levels is important.
Other functions
HERC2 helps to regulate p53 signalling by facilitating the oligomerization of
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 ...
, which is necessary for its transcriptional activity. Silencing of HERC2 reportedly inhibits the expression of genes regulated by p53 and also results in increased cellular growth.
Clinical significance
The 15q11-q13 locus of HERC2 is also associated with
Angelman syndrome
Angelman syndrome or Angelman's syndrome (AS) is a genetic disorder that mainly affects the nervous system. Symptoms include a small head and a specific facial appearance, severe intellectual disability, developmental disability, limited to no f ...
(AS), specifically when a region of this locus is deleted. Similar to the ''rjs'' phenotype attributed to HERC2 in mice, AS is associated with seizures, developmental delay, intellectual disability and jerky movements. While a variety of disturbances to this locus can cause AS, all known mechanisms affect the functioning and expression of the E6AP E3 ligase, which also sits at this locus. HER2 is an allosteric activator of E6AP, and lies at the most commonly deleted region in AS.
Its deletion could result in the inactivation of E6AP and consequently the development of AS.
In
Old Order Amish
The Amish (; pdc, Amisch; german: link=no, Amische), formally the Old Order Amish, are a group of traditionalist Anabaptist Christian church fellowships with Swiss German and Alsatian origins. They are closely related to Mennonite church ...
families, a homozygous proline to leucine missense mutation within the first RLD domain has been implicated in a neurodevelopmental disorder with
autism
The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...
and features resembling AS. In addition, a homozygous deletion of both OCA2 and HERC2 genes was recently reported as presenting with severe developmental abnormalities. These phenotypes are suggestive of a role for HERC2 in normal neurodevelopment.
Certain alleles of HERC2 has recently been implicated in increasing the risk of iris cancer. Due its role in pigment determination, three HERC2 SNPs have been highlighted as associated with
uveal melanoma
Uveal melanoma is a type of eye cancer in the uvea of the eye. It is traditionally classed as originating in the Iris (anatomy), iris, choroid, and ciliary body, but can also be divided into class I (low metastatic risk) and class II (high metasta ...
. HERC2 frameshift mutations have also been described in
colorectal cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...
s.
In accordance to its role in facilitating p53 oligomerization, HERC2 may be causally related to
Li-Fraumeni syndrome and Li-Fraumeni-like syndromes, which occur in the absence of sufficient p53 oligomerization.
Interactions
HERC2 is known to interact with the following:
*
RNF8
E3 ubiquitin-protein ligase RNF8 is an enzyme that in humans is encoded by the ''RNF8'' gene. RNF8 has activity both in immune system functions and in DNA repair.
Function
The protein encoded by this gene contains a RING finger motif and an ...
*
FBXL5
F-box/LRR-repeat protein 5 is a protein that in humans is encoded by the ''FBXL5'' gene.
This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitu ...
*
OCA2
P protein, also known as melanocyte-specific transporter protein or pink-eyed dilution protein homolog, is a protein that in humans is encoded by the oculocutaneous albinism II (''OCA2'') gene. The P protein is believed to be an integral membrane ...
*
UBC13
*
USP20
Ubiquitin carboxyl-terminal hydrolase 20 is an enzyme that in humans is encoded by the ''USP20'' gene.
Ubiquitin-specific protease 20 (USP20), also known as ubiquitin-binding protein 20 and VHL protein-interacting deubiquitinating enzyme 2 (VDU2), ...
*
XPA
DNA repair protein complementing XP-A cells is a protein that in humans is encoded by the ''XPA'' gene. Function
Nucleotide excision repair (NER) is a major pathway for repairing a variety of bulky DNA damages including those introduced by UV i ...
*
Claspin
*
E6AP
Ubiquitin-protein ligase E3A (UBE3A) also known as E6AP ubiquitin-protein ligase (E6AP) is an enzyme that in humans is encoded by the ''UBE3A'' gene. This enzyme is involved in targeting proteins for degradation within cells.
Protein degradation ...
*
NEURL4
*
RNF168
*
BRCA1
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a h ...
*
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 ...
*
LRRK2
Leucine-rich repeat kinase 2 (LRRK2), also known as dardarin (from the Basque word "dardara" which means trembling) and PARK8 (from early identified association with Parkinson's disease), is a large, multifunctional kinase enzyme that in humans i ...
See also
*
Angelman Syndrome
Angelman syndrome or Angelman's syndrome (AS) is a genetic disorder that mainly affects the nervous system. Symptoms include a small head and a specific facial appearance, severe intellectual disability, developmental disability, limited to no f ...
*
Eye color
Eye color is a polygenic phenotypic character determined by two distinct factors: the pigmentation of the eye's iris and the frequency-dependence of the scattering of light by the turbid medium in the stroma of the iris.
In humans, the pi ...
*
DNA repair pathways
References
Further reading
*
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{{Commons category, HERC2
Ligases