Biology:HERC2

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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 HECT domains and one or more RCC1-like (RLD) domains.[1][2]

History

HERC2, previously referred to as the rjs gene locus, was first identified in 1990 as the gene responsible for two phenotypes in mice: the runty, jerky, sterile (rjs) phenotype and the juvenile development and fertility-2 (Jdf2) phenotype. Mutant alleles 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.[3][4][5]

Gene locus

The full HERC2 gene is located at 15q13, encoded by 93 exons 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.[6]

At least 15 HERC2 SNPs have been identified and they are strongly associated with human iris colour variability, functioning to repress expression of OCA2's product.[7]

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.[8]

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.[1] This is likely involved in protein binding, and has recently been identified as a SUMOylation target following DNA damage.[9]

Expression of HERC2 is ubiquitous, though particularly high in the brain and testes. Cellular localisation is predominantly to the nucleus and cytoplasm.[1]

The third RLD domain of HERC2, captured at 1.8 Å by X-ray diffraction (3KCI)
The cytochrome-b5-like domain of HERC2, captured with NMR spectroscopy (2KEO)
The first RLD domain of HERC2, captured at 2.6 Å by X-ray diffraction (4L1M)

Protein function

Pigmentation

SNPs of HERC2 are strongly associated with 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 and hair colour. The ancestral allele is linked to darker pigmentation and dominant over the lighter pigment recessive allele.[10][11] 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.[12] This genotype is present in almost all people with blue eyes and is hypothesised as being the founder mutation of blue eyes in humans.[13][14][15]

The rs916977 SNP is most common in Europe; particularly in the north and east, where it nears fixation. The variant is also found at high frequencies in North Africa, the Near East, Oceania and the Americas.[16]

DNA repair pathways

HERC2 is a component of the replication fork 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.[17]

It is involved in coordinating the Chk1-directed DNA damage/cell cycle checkpoint response by regulating the stability of the deubiquitination enzyme USP20. Under normal conditions HERC2 associates with USP20 and ubiquitinates it for degradation. Under replication stress, for example a DNA polymerase 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.[18][19][20]

At the site of doubles stranded breaks, HERC2 facilitates the binding of RNF8, 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.[21]

HERC2 is also involved in regulating nucleotide excision repair by ubiquitinating the XPA 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.[22][23]

Centrosome assembly

HERC2 has been implicated in regulating stable centrosome architecture in conjunction with NEURL4 other ubiquitinated binding partners. Its absence is associated with aberrant centrosome morphology.[24]

Iron metabolism

HERC2 has recently been associated with regulating iron metabolism through ubiquitinating the F-box and leucine-rich repeat protein 5 (FBXL5) 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.[25]

Other functions

HERC2 helps to regulate p53 signalling by facilitating the oligomerization of p53, 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.[26]

Clinical significance

The 15q11-q13 locus of HERC2 is also associated with Angelman syndrome (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.[27] Its deletion could result in the inactivation of E6AP and consequently the development of AS.[28]

In Old Order Amish families, a homozygous proline to leucine missense mutation within the first RLD domain has been implicated in a neurodevelopmental disorder with autism and features resembling AS.[29] In addition, a homozygous deletion of both OCA2 and HERC2 genes was recently reported as presenting with severe developmental abnormalities.[30] 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.[31] HERC2 frameshift mutations have also been described in colorectal cancers.[32]

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.[26]

Interactions

HERC2 is known to interact with the following:

See also

References

  1. ↑ 1.0 1.1 1.2 "Functional and pathological relevance of HERC family proteins: a decade later". Cellular and Molecular Life Sciences 73 (10): 1955–68. May 2016. doi:10.1007/s00018-016-2139-8. PMID 26801221. 
  2. ↑ "The human HERC family of ubiquitin ligases: novel members, genomic organization, expression profiling, and evolutionary aspects". Genomics 85 (2): 153–64. February 2005. doi:10.1016/j.ygeno.2004.10.006. PMID 15676274. 
  3. ↑ "A very large protein with diverse functional motifs is deficient in rjs (runty, jerky, sterile) mice". Proceedings of the National Academy of Sciences of the United States of America 95 (16): 9436–41. August 1998. doi:10.1073/pnas.95.16.9436. PMID 9689098. Bibcode: 1998PNAS...95.9436L. 
  4. ↑ "The ancestral gene for transcribed, low-copy repeats in the Prader-Willi/Angelman region encodes a large protein implicated in protein trafficking, which is deficient in mice with neuromuscular and spermiogenic abnormalities". Human Molecular Genetics 8 (3): 533–42. March 1999. doi:10.1093/hmg/8.3.533. PMID 9949213. 
  5. ↑ "The mouse pink-eyed dilution locus: a model for aspects of Prader-Willi syndrome, Angelman syndrome, and a form of hypomelanosis of Ito". Mammalian Genome 3 (4): 187–91. 1992. doi:10.1007/bf00355717. PMID 1611213. 
  6. ↑ "Structure of the highly conserved HERC2 gene and of multiple partially duplicated paralogs in human". Genome Research 10 (3): 319–29. March 2000. doi:10.1101/gr.10.3.319. PMID 10720573. 
  7. ↑ "Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene". American Journal of Human Genetics 82 (2): 411–23. February 2008. doi:10.1016/j.ajhg.2007.10.003. PMID 18252221. 
  8. ↑ "A novel strategy for NMR resonance assignment and protein structure determination". Journal of Biomolecular NMR 49 (1): 27–38. January 2011. doi:10.1007/s10858-010-9458-0. PMID 21161328. 
  9. ↑ "DNA damage-inducible SUMOylation of HERC2 promotes RNF8 binding via a novel SUMO-binding Zinc finger". The Journal of Cell Biology 197 (2): 179–87. April 2012. doi:10.1083/jcb.201106152. PMID 22508508. 
  10. ↑ "Interactions between HERC2, OCA2 and MC1R may influence human pigmentation phenotype". Annals of Human Genetics 73 (2): 160–70. March 2009. doi:10.1111/j.1469-1809.2009.00504.x. PMID 19208107. 
  11. ↑ "Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression". Human Genetics 123 (2): 177–87. March 2008. doi:10.1007/s00439-007-0460-x. PMID 18172690. 
  12. ↑ "Genetics of human iris colour and patterns". Pigment Cell & Melanoma Research 22 (5): 544–62. October 2009. doi:10.1111/j.1755-148X.2009.00606.x. PMID 19619260. http://www.bashaar.org.il/files/4150.pdf. 
  13. ↑ Bryner J (2008-01-31). "Here's what made those brown eyes blue". Health News. NBC News. http://www.nbcnews.com/id/22934464. ; Bryner J (2008-01-31). "One Common Ancestor Behind Blue Eyes". LiveScience. Imaginova Corp.. http://www.livescience.com/health/080131-blue-eyes.html. ; "Blue-eyed humans have a single, common ancestor". News. University of Copenhagen. 2008-01-30. http://www.ku.dk/english/news/?content=http://www.ku.dk/english/news/blue-eyes.htm. 
  14. ↑ "A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color". American Journal of Human Genetics 82 (2): 424–31. February 2008. doi:10.1016/j.ajhg.2007.11.005. PMID 18252222. 
  15. ↑ 15.0 15.1 "A global view of the OCA2-HERC2 region and pigmentation". Human Genetics 131 (5): 683–96. May 2012. doi:10.1007/s00439-011-1110-x. PMID 22065085. 
  16. ↑ "Allele Frequency For Polymorphic Site: rs916977". ALFRED. https://alfred.med.yale.edu/alfred/SiteTable1A_working.asp?siteuid=SI663423Y. 
  17. ↑ "DNA repair excision nuclease attacks undamaged DNA. A potential source of spontaneous mutations". The Journal of Biological Chemistry 276 (27): 25421–6. July 2001. doi:10.1074/jbc.M101032200. PMID 11353769. 
  18. ↑ 18.0 18.1 18.2 "HERC2/USP20 coordinates CHK1 activation by modulating CLASPIN stability". Nucleic Acids Research 42 (21): 13074–81. December 2014. doi:10.1093/nar/gku978. PMID 25326330. 
  19. ↑ 19.0 19.1 19.2 "HERC2-USP20 axis regulates DNA damage checkpoint through Claspin". Nucleic Acids Research 42 (21): 13110–21. December 2014. doi:10.1093/nar/gku1034. PMID 25355518. 
  20. ↑ 20.0 20.1 "HERC2 Interacts with Claspin and regulates DNA origin firing and replication fork progression". Cancer Research 71 (17): 5621–5. September 2011. doi:10.1158/0008-5472.CAN-11-0385. PMID 21775519. 
  21. ↑ 21.0 21.1 21.2 21.3 "HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes" (in En). Nature Cell Biology 12 (1): 80–6; sup pp 1–12. January 2010. doi:10.1038/ncb2008. PMID 20023648. 
  22. ↑ 22.0 22.1 "Coordinated regulation of XPA stability by ATR and HERC2 during nucleotide excision repair" (in En). Oncogene 33 (1): 19–25. January 2014. doi:10.1038/onc.2012.539. PMID 23178497. 
  23. ↑ 23.0 23.1 "Circadian control of XPA and excision repair of cisplatin-DNA damage by cryptochrome and HERC2 ubiquitin ligase". Proceedings of the National Academy of Sciences of the United States of America 107 (11): 4890–5. March 2010. doi:10.1073/pnas.0915085107. PMID 20304803. Bibcode: 2010PNAS..107.4890K. 
  24. ↑ 24.0 24.1 "Interaction proteomics identify NEURL4 and the HECT E3 ligase HERC2 as novel modulators of centrosome architecture". Molecular & Cellular Proteomics 11 (6): M111.014233. June 2012. doi:10.1074/mcp.M111.014233. PMID 22261722. 
  25. ↑ 25.0 25.1 "HERC2 targets the iron regulator FBXL5 for degradation and modulates iron metabolism". The Journal of Biological Chemistry 289 (23): 16430–41. June 2014. doi:10.1074/jbc.M113.541490. PMID 24778179. 
  26. ↑ 26.0 26.1 26.2 "The E3 ubiquitin protein ligase HERC2 modulates the activity of tumor protein p53 by regulating its oligomerization". The Journal of Biological Chemistry 289 (21): 14782–95. May 2014. doi:10.1074/jbc.M113.527978. PMID 24722987. 
  27. ↑ 27.0 27.1 "Physical and functional interaction of the HECT ubiquitin-protein ligases E6AP and HERC2". The Journal of Biological Chemistry 286 (22): 19410–6. June 2011. doi:10.1074/jbc.M110.205211. PMID 21493713. 
  28. ↑ "Mutation of HERC2 causes developmental delay with Angelman-like features". Journal of Medical Genetics 50 (2): 65–73. February 2013. doi:10.1136/jmedgenet-2012-101367. PMID 23243086. https://kops.uni-konstanz.de/bitstream/123456789/21937/2/Harlalka_219370.pdf. 
  29. ↑ "A homozygous missense mutation in HERC2 associated with global developmental delay and autism spectrum disorder". Human Mutation 33 (12): 1639–46. December 2012. doi:10.1002/humu.22237. PMID 23065719. 
  30. ↑ "Complete loss of function of the ubiquitin ligase HERC2 causes a severe neurodevelopmental phenotype" (in En). European Journal of Human Genetics 25 (1): 52–58. January 2016. doi:10.1038/ejhg.2016.139. PMID 27759030. 
  31. ↑ "Genetic markers of pigmentation are novel risk loci for uveal melanoma". Scientific Reports 6 (1): 31191. August 2016. doi:10.1038/srep31191. PMID 27499155. Bibcode: 2016NatSR...631191F. 
  32. ↑ "Frameshift mutations of ubiquitination-related genes HERC2, HERC3, TRIP12, UBE2Q1 and UBE4B in gastric and colorectal carcinomas with microsatellite instability". Pathology 43 (7): 753–5. December 2011. doi:10.1097/pat.0b013e32834c7e78. PMID 22124266. 
  33. ↑ "HERC2 is an E3 ligase that targets BRCA1 for degradation". Cancer Research 70 (15): 6384–92. August 2010. doi:10.1158/0008-5472.CAN-10-1304. PMID 20631078. 
  34. ↑ "The Parkinson's Disease-Associated Protein Kinase LRRK2 Modulates Notch Signaling through the Endosomal Pathway". PLOS Genetics 11 (9): e1005503. September 2015. doi:10.1371/journal.pgen.1005503. PMID 26355680. 

Further reading



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