Ph.D., University of Tokyo, Medicine, 1999.
M.D., University of Tokyo, 1990.
Major research interests of our laboratory are:
1. Fanconi anemia and cancer susceptibility
2. DNA repair and cell cycle checkpoints
3. Drug sensitivity and resistance in cancer chemotherapy
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 recessive (or X-linked) 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 15 complementation groups (FA-A, B, C, D1, D2, E, F, G, I, J, L, M, N, O and P) and all of the 15 FA genes (FANCA, B, C, D1(BRCA2), D2, E, F, G, I, J(BACH1/BRIP1), L, M, N(PALB2), O(RAD51C) and P(SLX4)) 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. Eight FA proteins (A, B, C, E, F, G, L and M) are components of a multi-subunit ubiquitin ligase complex (FA core complex) required for the monoubiquitination of FANCD2. FANCI and FANCD2 form another protein complex called the ID complex.
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. Furthermore, reactivation of the FA-BRCA pathway can contribute to acquired resistance to cisplatin and PARP inhibitors in FA-BRCA pathway-deficient cancer cells. For example, we found that restoration of functional BRCA1/2 proteins due to secondary mutations in BRCA1/2 can lead to acquired resistance to platinum compounds in BRCA1/2-mutated ovarian carcinomas.
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.
1. Identification of novel factors (genes, microRNAs) involved in the FA-BRCA pathway
2. Elucidation of the function of the FA pathway in cell cycle checkpoints and in DNA repair
Clinical application of the basic science of FA.
1. The FA pathway in the pathogenesis of cancer
2. Identification of small molecules as FA pathway inhibitors and agonists
3. Cisplatin resistance and the FA pathway
Current lab members
Toshiyasu Taniguchi - PI
Kanan Lathia - Research Technician
Celine Jacquemont - Postdoctoral fellow
Kiranjit Dhillon - Postdoctoral fellow
Maria Castella - Postdoctoral fellow
Ronald Cheung - Postdoctoral fellow
Jen-Wei Huang - MCB graduate student
Philamer Calses - MCB graduate student
Antonio Abeyta - MCB graduate student
(Reading, Writing, Speaking)
English: (Fluent, Fluent, Fluent)
Japanese: (Fluent, Fluent, Fluent)
American Association for Cancer Research
American Society of Hematology
Honors and Awards
2009-2015, HHMI Early Career Scientist, HHMI
2005-2008, Searle Scholar Award, Searle Funds, Fred Hutchinson Cancer Research Center
2005-2007, V Scholar Award, V Foundation for Cancer Research, Fred Hutchinson Cancer Research Center
2002-2004, ASH Fellow Scholar Award - Basic Research, American Society of Hematology, Dana-Farber Cancer Institute
1999-2000, Naito Foundation Fellowship for Research Abroad, Naito Foundation, Dana-Farber Cancer Institute
2002-2004, Instructor, Dana-Farber Cancer Institute, Clinical and Basic Science Research, Pediatric Oncology
1999-2002, Postdoctoral Fellow, Dana-Farber Cancer Institute, Clinical and Basic Science Research, Pediatric Oncology
Synthetic lethality: the road to novel therapies for breast cancer.. Endocrine-related cancer. 23(10):T39-T55.. 2016.
NEK8 regulates DNA damage-induced RAD51 foci formation and replication fork protection.. Cell cycle (Georgetown, Tex.).. 2016.
Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L.. American journal of human genetics. 98(6):1146-58.. 2016.
BRCA1185delAG tumors may acquire therapy resistance through expression of RING-less BRCA1.. The Journal of clinical investigation. 126(8):2903-18.. 2016.
FANCI Regulates Recruitment of the FA Core Complex at Sites of DNA Damage Independently of FANCD2.. PLoS genetics. 11(10):e1005563.. 2015.
p53 is positively regulated by miR-542-3p.. Cancer research. 74(12):3218-27.. 2014.
53BP1 expression in sporadic and inherited ovarian carcinoma: Relationship to genetic status and clinical outcomes.. Gynecologic oncology. 128(3):493-9.. 2013.
Systematic Screen Identifies miRNAs that Target RAD51 and RAD51D to Enhance Chemosensitivity.. Molecular cancer research : MCR. 11(12):1564-73.. 2013.
Molecular scores to predict ovarian cancer outcomes: a worthy goal, but not ready for prime time.. Journal of the National Cancer Institute. 104(9):642-5.. 2012.
Non-specific chemical inhibition of the Fanconi anemia pathway sensitizes cancer cells to cisplatin.. Molecular cancer. 11(1):26.. 2012.
Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas.. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 29(22):3008-15.. 2011.
MicroRNA-138 Modulates DNA Damage Response by Repressing Histone H2AX Expression.. Molecular cancer research : MCR. 9(8):1100-11.. 2011.
Secondary mutations of BRCA1/2 and drug resistance.. Cancer science. 102(4):663-9.. 2011.
Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer.. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 28(22):3555-61.. 2010.
Functional restoration of BRCA2 protein by secondary BRCA2 mutations in BRCA2-mutated ovarian carcinoma.. Cancer research. 69(16):6381-6.. 2009.
Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers.. Nature. 451(7182):1116-20.. 2008.
Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance.. Cancer research. 68(8):2581-6.. 2008.