Research ToolsHow can FANCL be studied?To gain more insight into the function of FANCL, further research must be done to understand the affects mutations have on the protein's ability to function in the Fanconi Anemia pathway. To achieve this, research must be done within model organisms or in cell cultures to be able to manipulate the gene to understand the effects of particular mutations. Utilizing model organisms, studies with chemical genetics and analysis with gene expression microarrays have the potential to provide more information about FANCL-cause Fanconi Anemia.
Utilizing Model OrganismsWith ethical constraints in understanding disease in humans, model organisms have been used for decades to manipulate the genome to determine the direct cause of diseases. Concerted efforts around the world have created databases for model organisms to provide valuable information about past and present experimentation and two important databases are Mouse Genome Informatics (MGI) and the Zebrafish Model Organism Database (ZFIN) [1,2]. These two databases can provide valuable information about FANCL because both mice and zebrafish were found to have homologous FANCL proteins. Detailed below, there are entries into the MGI and ZFIN databases for FANCL that detail genotypes, phenotypes, mutants, and more.
Gene Expression MicroarraysThe Gene Expression Omnibus (GEO) is part of the NCBI suite of databases and is provides Datasets from microarray experiments [3]. The GEO profiles database provides GEO profiles that show the expression levels of proteins under experimental conditions measured by these microarrays. By analyzing these profiles, differential expression patterns of a protein can be understood.
Because FANCL-cause Fanconi Anemia is the direct result of the lack of FANCL, GEO profiles detailing this condition would not provide any valuable information. In contrast, Fanconi Anemia caused by mutations to another FA protein may result in differential expression of FANCL, but unfortunately no such GEO profiles exist for this type of experiment.
In an attempt to utilize the GEO database to find differential expression tendencies across the group of FA proteins, an experiment came up looking at a model of skin carcinogenesis in mice comparing gene expression between mice with a wild type ATF-2 protein and a ATF-2 knockout [4]. The GEO profile indicated a greater than 50% reduction in FANCL expression in ATF-2 knockout mice. Looking to gain more information on all the complementation groups, an in-depth analysis of the cluster analysis of the dataset showed a potentially interesting result. In the experiment, the differential gene expression pattern was relatively correlated between the FA proteins, which could be an interesting lead into further experimentation into FA protein coordinated gene regulation.
Analysis of ResultsBy using model organisms, specifically Mus musculus like in the above two experiments, a better understanding of the interactions of the FANCL protein with the FA core complex proteins and the ID complex can be studied experimentally. With this in mind, a focus for research is the effect that mutations have on the WD repeat domain and the RING finger domain. With the information available in the MGI database, mutant FANCL homologs can be found and utilized in studies that can relate back to the gene expression microarray analysis and chemical genetics screen proposed above. In particular, mutations to the WD repeat domain may affect the correlation seen in the gene expression microarray experiment and mutations to the RING finger domain may affect the binding of the domain to a small molecule that may be able to modulate the protein's function.
|
References
[1] Mouse Genome Informatics
[2] The Zebrafish Model Organism Database
[3] GEO Profile database browser
[4] Bhoumik A, Fichtman B, Derossi C, Breitwieser W et al. Suppressor role of activating transcription factor 2 (ATF2) in skin cancer. Proc Natl Acad Sci U S A 2008 Feb 5;105(5):1674-9. PMID: 18227516
[2] The Zebrafish Model Organism Database
[3] GEO Profile database browser
[4] Bhoumik A, Fichtman B, Derossi C, Breitwieser W et al. Suppressor role of activating transcription factor 2 (ATF2) in skin cancer. Proc Natl Acad Sci U S A 2008 Feb 5;105(5):1674-9. PMID: 18227516
Image Resources
Figure 1: MGI logo
Figure 2: ZFIN logo
Figure 3: GEO logo
Figure 4: GEO profile of FANCL
Figure 5: Cluster analysis of FANC proteins
Figure 6: Pubchem logo
Figure 2: ZFIN logo
Figure 3: GEO logo
Figure 4: GEO profile of FANCL
Figure 5: Cluster analysis of FANC proteins
Figure 6: Pubchem logo