User:Rockpocket/Rad18
E3 ubiquitin-protein ligase RAD18 is an enzyme that in humans is encoded by the RAD18 gene.[1][2][3]
The protein encoded by this gene is highly similar to S. cerevisiae DNA damage repair protein Rad18. Yeast Rad18 functions through its interaction with Rad6, which is a ubiquitin-conjugating enzyme required for post-replication repair of damaged DNA. Similar to its yeast counterpart, this protein is able to interact with the human homolog of yeast Rad6 protein through a conserved ring-finger motif. Mutation of this motif results in defective replication of UV-damaged DNA and hypersensitivity to multiple mutagens.[3]
Animal models
[edit]Model organisms have been used in the study of RAD18 function. A conditional knockout mouse line, called Rad18tm1a(EUCOMM)Wtsi,[4] was generated as part of the EUCOMM program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[5][6][7][8] Mice lacking Rad18 had no significant defects in viability or fertility,[9][10] therefore male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[5][11][12]
| Characteristic | Abnormal |
|---|---|
| Homozygote viability | No |
| Fertility | No |
| Body weight | Yes[13] |
| Hair follicle cycling | No |
| Anxiety | No |
| Modified SHIRPA | No |
| Grip strength | No |
| Dysmorphology | No |
| Indirect calorimetry | Yes[14] |
| Glucose tolerance test | No |
| Auditory brainstem response | No |
| DEXA | Yes[15] |
| Radiography | No |
| Body temperature | No |
| Eye morphology | No |
| Heart weight | No |
| Heart histology | No |
| Histology | No |
| Clinical chemistry | No |
| Plasma immunoglobulins | No |
| Haematology | No |
| Peripheral blood lymphocytes | No |
| Micronucleus test | Yes[12] |
| Salmonella infection | No |
| Citrobacter infection | No |
| All tests and analysis from [11][12] | |
Twenty four tests were carried out and four significant phenotypes were reported:[12]
- Mutant male mice had a decreased body weight compared to wildtype control mice.
- Mutant male mice showed increased activity, VO2 and energy expenditure, determined by indirect calorimetry.
- Dual-energy X-ray absorptiometry (DEXA) showed mutant male mice had a decrease in fat mass.
- A micronucleus test found a potential increase in DNA damage in mutant mice.
Interactions
[edit]RAD18 has been shown to interact with HLTF,[16] UBE2B[2][1] and UBE2A.[2][1]
References
[edit]- ^ a b c Tateishi S, Sakuraba Y, Masuyama S, Inoue H, Yamaizumi M (Aug 2000). "Dysfunction of human Rad18 results in defective postreplication repair and hypersensitivity to multiple mutagens". Proc Natl Acad Sci U S A. 97 (14): 7927–32. doi:10.1073/pnas.97.14.7927. PMC 16647. PMID 10884424.
{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link) Cite error: The named reference "pmid10884424" was defined multiple times with different content (see the help page). - ^ a b c Xin H, Lin W, Sumanasekera W, Zhang Y, Wu X, Wang Z (Sep 2000). "The human RAD18 gene product interacts with HHR6A and HHR6B". Nucleic Acids Res. 28 (14): 2847–54. doi:10.1093/nar/28.14.2847. PMC 102657. PMID 10908344.
{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link) Cite error: The named reference "pmid10908344" was defined multiple times with different content (see the help page). - ^ a b "Entrez Gene: RAD18 RAD18 homolog (S. cerevisiae)".
- ^ EUCOMM. "Rad18tm1a(EUCOMM)Wtsi". www
.knockoutmouse .org. Retrieved 7 March 2011. {{cite web}}: External link in|publisher= - ^ a b Van der Weyden L, White JK, Adams, DA, Logan DW (June 2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMID 21722353.
{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - ^ Dolgin E (June 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–263. doi:10.1038/474262a. PMID 21677718.
{{cite journal}}: CS1 maint: date and year (link) - ^ Collins FS, Rossant J, Wurst W (January 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link) - ^ Auwerx J, Avner P, Baldock R; et al. (September 2004). "The European dimension for the mouse genome mutagenesis program". Nat. Genet. 36 (9): 925–7. doi:10.1038/ng0904-925. PMC 2716028. PMID 15340424.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link) - ^ Wellcome Trust Sanger Institute. "Viability at Weaning Data for Rad18". Mouse Resources Portal. www
.sanger .ac .uk. Retrieved 7 March 2011. {{cite web}}: External link in|publisher= - ^ Wellcome Trust Sanger Institute. "Fertility Data for Rad18". Mouse Resources Portal. www
.sanger .ac .uk. Retrieved 7 March 2011. {{cite web}}: External link in|publisher= - ^ a b Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
- ^ a b c d Wellcome Trust Sanger Institute. "MGP Phenotyping of Rad18tm1a(EUCOMM)Wtsi". Mouse Resources Portal. www
.sanger .ac .uk. Retrieved 7 March 2011. {{cite web}}: External link in|publisher= - ^ Wellcome Trust Sanger Institute. "Weight Curves Data for Rad18". Mouse Resources Portal. www
.sanger .ac .uk. Retrieved 7 March 2011. {{cite web}}: External link in|publisher= - ^ Wellcome Trust Sanger Institute. "Indirect Calorimetry Data for Rad18". Mouse Resources Portal. www
.sanger .ac .uk. Retrieved 7 March 2011. {{cite web}}: External link in|publisher= - ^ Wellcome Trust Sanger Institute. "Body Composition (DEXA) Data for Rad18". Mouse Resources Portal. www
.sanger .ac .uk. Retrieved 7 March 2011. {{cite web}}: External link in|publisher= - ^ Unk, Ildiko; Hajdú, Ildikó; Fátyol, Károly; Hurwitz, Jerard; Yoon, Jung-Hoon; Prakash, Louise; Prakash, Satya; Haracska, Lajos (2008). "Human HLTF functions as a ubiquitin ligase for proliferating cell nuclear antigen polyubiquitination". Proc. Natl. Acad. Sci. U.S.A. 105 (10). United States: 3768–73. doi:10.1073/pnas.0800563105. PMC 2268824. PMID 18316726.
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