Toshiyasu Taniguchi

Appointments and Affiliations

 
 
Fred Hutchinson Cancer Research Center
Human Biology Division
Associate Member, Appointed: 2004
Howard Hughes Medical Institute
HHMI Early Career Scientist, Appointed: 2009
University of Washington
School of Medicine
Pathology
Affiliate Associate Professor, Appointed: 2008
Professional Headshot of Toshiyasu  Taniguchi

Mailing Address

1100 Fairview Avenue N. C1-015
Seattle, Washington 98109-1024
United States

Degrees

Ph.D., University of Tokyo, Medicine, 1999.
M.D., University of Tokyo, 1990.

Research Interests

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

Languages

(Reading, Writing, Speaking)

English: (Fluent, Fluent, Fluent)
Japanese: (Fluent, Fluent, Fluent)

Memberships

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

Previous Positions

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

Funding

  • National Institutes of Health (NIH): Project #4 in ovarian cancer SPORE P50 CA083636 , Clinical implication of the acquisition of BRCA1/2 function in BRCA1/2-deficient ovarian carcinoma, 2009 to 2014.
  • HHMI: HHMI Early Career Scientist Award, 2009 to 2015.
  • Fanconi Anemia Research Fund: , 2008 to 2009.
  • FHCRC/UW Cancer Consortium: 2008 CCSG Pilot Grant, 2008 to 2008.
  • Marsha Rivkin Center for Ovarian Cancer Research: Pilot Study Program Grant, 2008 to 2009.
  • NIH/NHLBI, R21: ', 2008 to 2010.
  • National Institutes of Health/National Cancer Institute, RO1: The Fanconi Anemia-BRCA Pathway and Chemosensitivity of Human Cancer, 2007 to 2012.
  • Hartwell Innovation Fund: Significance of genetic reversion in acquired cisplatin resistance of BRCA1/2-mutated cancer, 2006 to 2007.
  • Searle Scholars Program: Analysis of the Fanconi Anemia-BRCA Pathway in Cancer, 2005 to 2008.
  • Mary Kay Ash Charitable Foundation: Sensitization of ovarian cancer cells to chemotherapy by modulating the Fanconi Anemia-BRCA Pathway, 2005 to 2007.
  • The V Foundation for Cancer Research: Mechanism of BRCA2/FANCD1 protein inactivation/reactivation in ovarian cancer cells during cisplatin treatment, 2005 to 2007.
  • AVON Breast Cancer Crusade Opportunity Fund (Pilot Project Fund for Innovative Breast Cancer Research): Analysis of the Fanconi Anemia Protein, FANCF, in Breast Cancer, 2005 to 2006.
  • American Society of Hematology (ASH Fellow Scholar Award - Basic Research ): Functional Analysis of the Fanconi Anemia Proteins, 2002 to 2004.

 

Recent Publications

2014
2013
2012
2011
2010
2009
2008