Fanconi anemia and DNA Repair
Fanconi anemia (FA) is a rare genetic disease characterized by aplastic anemia, developmental defects and cancer susceptibility. FA can be divided into at least 22 complementation groups, and all of the responsible genes for these groups (FA genes) have been identified. The breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2, are also FA genes. Proteins encoded by these FA genes cooperate in a common DNA repair pathway, called the FA-BRCA pathway or the FA pathway. The FA-BRCA pathway is needed to protect cells from DNA damage created by interstrand DNA-crossliking agents, such as cisplatin and carboplatin (platinum compounds). Cells with defects in the FA-BRCA pathway are sensitive to killing by these platinum compounds. The platinum compounds are commonly used to treat ovarian, testicular, and other solid tumors and are particularly effective in tumors with defective FA-BRCA pathway. Thus, understanding the molecular biology of the FA-BRCA pathway can help refine the diagnosis and therapy of patients with cancer or with Fanconi anemia.
We are interested in identifying novel genes involved in the FA-BRCA pathway and understanding the functions of these genes in DNA repair. We are also interested in how the pathway is regulated by posttranslational modifications, such as phosphorylation and ubiquitination.
We would also like to determine the role of the FA-BRCA pathway in the pathogenesis of cancer and to identify small molecule inhibitors or agonists of the FA-BRCA pathway that may be used as novel chemotherapeutic agents or help increase clinical effectiveness of existing chemotherapeutic agents. Read more…
Drug Sensitivity and Resistance in Cancer Chemotherapy
Interstrand DNA crosslinking agents, such as cisplatin and carboplatin, have been used as effective chemotherapy for ovarian and other solid tumors. However, resistance to these drugs poses a significant challenge for treatment of recurrent tumors. Understanding mechanisms that lead to drug resistance is an important step to ameliorate this problem. We have studied this problem in the context of BRCA1/BRCA2-deficient cancers and found that secondary mutations of BRCA1/2 which restore functional BRCA1/2 can be a mechanism of acquired resistance to platinum compounds and PARP inhibitors in BRCA1/2-mutated cancers. There will be other mechanisms of acquired resistance to these drugs, and we are trying to elucidate such mechanisms. Read more…
DGCR8-mediated UV response pathway
MicroRNAs regulate many biological processes, including DNA repair.
Ultraviolet (UV) causes DNA damage and is a carcinogen. DNA damaged by UV is repaired by nucleotide excision repair (NER) in mammalian cells.
DGCR8 is an RNA-binding protein, which is known to play a critical role in microRNA biogenesis. Recently, we found that DGCR8 is involved in cellular resistance to UV light exposure and proposed a novel concept of “DGCR8-mediated UV response pathway.” In response to UV exposure to cells, DGCR8 protein is phosphorylated. This phosphorylation is critical for the repair of UV-induced DNA lesions by transcription-coupled NER. We termed this DGCR8-mediated UV response pathway.
We are studying mechanisms by which this pathway regulates transcription-coupled NER. This study will contribute to our understanding of UV-induced carcinogenesis and chemical-induced carcinogenesis. Read more…