Divisions of Human Biology & Public Health Sciences
Fred Hutchinson Cancer Research Center
1100 Fairview Ave., N., C1-015
Seattle, WA 98109-1024
2005 Searle Scholar
My major research interests are:
Studying rare genetic diseases with cancer susceptibility has been a productive way to get insights into pathogenesis of cancer in the general population. For example, mutations in p53, Rb, and ATM genes are responsible for the genetic diseases, Li-Fraumeni syndrome, familial retinoblastoma, and ataxia telangiectasia, respectively. Similarly, another rare cancer susceptibility syndrome called Fanconi anemia has more recently emerged in the DNA repair and signaling field. It has turned out that understanding this genetic disorder may greatly enhance our knowledge of the pathogenesis and progression of human cancers. Additionally, the Fanconi anemia pathway is an attractive model system for studying cancer, DNA repair and ubiquitin biology.
Genomic instability is a hallmark of most human cancers and is thought to be a main impetus behind premalignant cells transforming to a more malignant state through the acquisition of multiple somatic mutations. Defects of transforming the DNA damage response, such as activation of DNA repair and cell cycle checkpoints, can be a possible mechanism of genomic instability in cancer. It may also be responsible for the sensitivity of cancer cells to certain types of chemotherapeutic drugs and radiation. Thus, it is important to elucidate the cause of genomic instability and the mechanisms surrounding the DNA damage response pathway in order to achieve greater understanding of cancer and for developing new diagnostic and therapeutic strategies. The Fanconi anemia pathway plays a central role in preventing genomic instability.
Fanconi anemia (FA) is an autosomal (or X-linked) recessive cancer susceptibility syndrome characterized by chromosomal instability and cellular hypersensitivity to DNA crosslinking agents, such as cisplatin and mitomycin C. FA is comprised of at least 11 complementation groups (FA-A, B, C, D1, D2, E, F, G, I, J, and L) and 9 FA genes (FANCA, B, C, D1(BRCA2), D2, E, F, G, and L) have been identified. The breast/ovarian cancer susceptibility gene products (BRCA1 and BRCA2 proteins) and all of the FA proteins cooperate in a common pathway required for the cellular resistance to DNA crosslinking agents, and this pathway is now called "the Fanconi anemia-BRCA pathway."
The key event in the FA-BRCA pathway is the monoubiquitination of one of the FA proteins, FANCD2. Monoubiquitination (conjugation of one ubiquitin molecule onto a protein) is a rather newly recognized type of posttranslational modification. Seven FA proteins (A, B, C, E, F, G and L) are components of a multi-subunit ubiquitin ligase complex (FA core complex) required for the monoubiquitination of FANCD2.
In response to DNA damage, this FA-BRCA pathway gets activated. After DNA damage, FANCD2 gets monoubiquitinated and targeted to BRCA1/BRCA2/RAD51-containing nuclear foci at the sites of DNA damage. FA core complex, BRCA1 and a DNA damage signaling kinase called ATR are required for this process. Monoubiquitinated FANCD2 controls the localization of BRCA2 and affects the efficiency of homologous recombination, which is a way of repairing damaged DNA. After ionizing radiation (IR) exposure, FANCD2 is directly phosphorylated by another DNA damage signaling kinase called ATM, and this phosphorylation is required for the establishment of IR-inducible S phase checkpoint. Thus, the FA-BRCA pathway is a DNA damage-activated signaling pathway which controls DNA repair and cell cycle checkpoint.
Interestingly, the FA-BRCA pathway is inactivated in a wide variety of human cancers (ovarian, breast, non-small cell lung, cervical, and head and neck squamous cell cancers) by methylation of one of the FA genes, FANCF. This inactivation causes cisplatin-sensitivity, suggesting a broad and important role of the pathway in human carcinogenesis and chemosensitivity of cancer.
The long-term objective of our research is to elucidate molecular mechanism of DNA damage response pathways, such as the FA-BRCA pathway, and their involvement in carcinogenesis and to utilize such information to refine diagnosis and therapy of patients with cancer or with FA. Currently, our lab is focusing on the following projects regarding the FA-BRCA pathway:
Basic science of FA
Clinical application of the basic science of FA
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