8q0n

Structural highlights

Disease

HACE1_HUMAN Spastic paraplegia-severe developmental delay-epilepsy syndrome;Neuroblastoma. Defects in HACE1 are a cause of Wilms tumor (WT). WT is a pediatric malignancy of kidney and one of the most common solid cancers in childhood. HACE1 is epigenetically down-regulated in sporadic Wilms tumor. Moreover, a t(5;6)(q21;q21) translocation that truncates HACE1 has been found in a child with bilateral, young-onset Wilms tumor (PubMed:19948536).^{[1] [2]} The disease is caused by variants affecting the gene represented in this entry.

Function

HACE1_HUMAN E3 ubiquitin-protein ligase involved in Golgi membrane fusion and regulation of small GTPases. Acts as a regulator of Golgi membrane dynamics during the cell cycle: recruited to Golgi membrane by Rab proteins and regulates postmitotic Golgi membrane fusion. Acts by mediating ubiquitination during mitotic Golgi disassembly, ubiquitination serving as a signal for Golgi reassembly later, after cell division. Specifically interacts with GTP-bound RAC1, mediating ubiquitination and subsequent degradation of active RAC1, thereby playing a role in host defense against pathogens. May also act as a transcription regulator via its interaction with RARB.^{[3] [4] [5]}

References

1. ↑ Zhang L, Anglesio MS, O'Sullivan M, Zhang F, Yang G, Sarao R, Mai PN, Cronin S, Hara H, Melnyk N, Li L, Wada T, Liu PP, Farrar J, Arceci RJ, Sorensen PH, Penninger JM. The E3 ligase HACE1 is a critical chromosome 6q21 tumor suppressor involved in multiple cancers. Nat Med. 2007 Sep;13(9):1060-9. PMID:17694067 doi:10.1038/nm1621
2. ↑ Slade I, Stephens P, Douglas J, Barker K, Stebbings L, Abbaszadeh F, Pritchard-Jones K, Cole R, Pizer B, Stiller C, Vujanic G, Scott RH, Stratton MR, Rahman N. Constitutional translocation breakpoint mapping by genome-wide paired-end sequencing identifies HACE1 as a putative Wilms tumour susceptibility gene. J Med Genet. 2010 May;47(5):342-7. PMID:19948536 doi:10.1136/jmg.2009.072983
3. ↑ Anglesio MS, Evdokimova V, Melnyk N, Zhang L, Fernandez CV, Grundy PE, Leach S, Marra MA, Brooks-Wilson AR, Penninger J, Sorensen PH. Differential expression of a novel ankyrin containing E3 ubiquitin-protein ligase, Hace1, in sporadic Wilms' tumor versus normal kidney. Hum Mol Genet. 2004 Sep 15;13(18):2061-74. PMID:15254018 doi:10.1093/hmg/ddh215
4. ↑ Tang D, Xiang Y, De Renzis S, Rink J, Zheng G, Zerial M, Wang Y. The ubiquitin ligase HACE1 regulates Golgi membrane dynamics during the cell cycle. Nat Commun. 2011 Oct 11;2:501. PMID:21988917 doi:10.1038/ncomms1509
5. ↑ Torrino S, Visvikis O, Doye A, Boyer L, Stefani C, Munro P, Bertoglio J, Gacon G, Mettouchi A, Lemichez E. The E3 ubiquitin-ligase HACE1 catalyzes the ubiquitylation of active Rac1. Dev Cell. 2011 Nov 15;21(5):959-65. PMID:22036506 doi:10.1016/j.devcel.2011.08.015