Fanconi anemia (FA) is a genetic disorder characterized by progressive bone marrow failure and a predisposition to cancers like acute myeloid leukemia, lung and squamous cell carcinomas. DNA damage in a healthy cell activates the FA pathway where 15 individual FA proteins interact and function together to maintain genomic stability. The disruption of this pathway results in the characteristic cellular phenotype and clinical outcome of the disease. The diverse clinical symptoms of FA such as impaired immunity and predisposition to cancers may not be explained exclusively by a non-functional FA pathway. These symptoms could then be attributed to defects in other functions of the individual FA proteins.
a) Identification of novel target genes involved in Fanconi anemia using microarray of Indian patient samples
We have looked at the expression profile of FA patients from the Indian population, to pick up a consortium of genes that commonly represent themselves across FA patients irrespective of complementation groups.We carried out the first ever genome wide expression study for Indian FA samples and reported for the first time, down regulation of three target genes ATXN3, ARID4A and ETS-1. The dysregulation of these genes can provide explanations for oxygen sensitivity, certain aberrant hematological defects, and impaired immunity associated with FA.
b) Understanding the transcriptional regulatory role of FANCC and FANCA proteins in Fanconi anemia cell lines
To identify the effects of a mutant FA protein, we have employed a transcriptome analysis with a Fanconi anemia cell line and revertant isogenic control cell line. Microarray data revealed dysregulation of genes involved in regulation of cell death and immune response. We reported for the first time, the lowered expression of a tumor suppressor gene- caveolin-1, in FA mutant cells. The downregulation of caveolin-1 can be significant as Fanconi anemia patients have an elevated predisposition to develop cancer.To identify the effects of a mutant FA protein, we have employed a transcriptome analysis with a Fanconi anemia cell line and revertant isogenic control cell line. Microarray data revealed dysregulation of genes involved in regulation of cell death and immune response. We reported for the first time, the lowered expression of a tumor suppressor gene- caveolin-1, in FA mutant cells. The downregulation of caveolin-1 can be significant as Fanconi anemia patients have an elevated predisposition to develop cancer.
c) Role of Wnt and Notch signaling in the phenotypic symptoms of Fanconi anemia
Study of Cancer and developmental defects in Fanconi Anemia has remained a challenge to humanity due to its multiple genes of origin which makes it difficult to be targeted using a single drug therapy. Wnt and Notch signaling regulates many aspects of vertebrate development and adult stem cells. Deregulation of both signaling pathways causes development defect and cancer. Our lab focuses on identifying the dysregulated expression pattern of Wnt and Notch target genesin Fanconi Anemia and understand the various levels of regulation by these key moleculesin order to find alternative pathways of controlling cancer in Fanconi anemia.
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