Bio

Honors & Awards


  • Excellent Presentation Award, Japanese Society of Oral and Maxillofacial Surgeons (2013)
  • Travel Award, The Kyoto University Foundation (2012)
  • Young Scientists Program Award, IUBMB&FEBS (2012)

Professional Education


  • PhD, Kyoto University, Medical Science (2009)
  • Doctor, Kyushu Dental University, Dental Surgery (2002)

Stanford Advisors


Publications

Journal Articles


  • Molecular mechanism for generation of antibody memory PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES Shivarov, V., Shinkura, R., Doi, T., Begum, N. A., Nagaoka, H., Okazaki, I., Ito, S., Nonaka, T., Kinoshita, K., Honjo, T. 2009; 364 (1517): 569-575

    Abstract

    Activation-induced cytidine deaminase (AID) is the essential enzyme inducing the DNA cleavage required for both somatic hypermutation and class switch recombination (CSR) of the immunoglobulin gene. We originally proposed the RNA-editing model for the mechanism of DNA cleavage by AID. We obtained evidence that fulfils three requirements for CSR by this model, namely (i) AID shuttling between nucleus and cytoplasm, (ii) de novo protein synthesis for CSR, and (iii) AID-RNA complex formation. The alternative hypothesis, designated as the DNA-deamination model, assumes that the in vitro DNA deamination activity of AID is representative of its physiological function in vivo. Furthermore, the resulting dU was removed by uracil DNA glycosylase (UNG) to generate a basic site, followed by phosphodiester bond cleavage by AP endonuclease. We critically examined each of these provisional steps. We identified a cluster of mutants (H48A, L49A, R50A and N51A) that had particularly higher CSR activities than expected from their DNA deamination activities. The most striking was the N51A mutant that had no ability to deaminate DNA in vitro but retained approximately 50 per cent of the wild-type level of CSR activity. We also provide further evidence that UNG plays a non-canonical role in CSR, namely in the repair step of the DNA breaks. Taking these results together, we favour the RNA-editing model for the function of AID in CSR.

    View details for DOI 10.1098/rstb.2008.0183

    View details for Web of Science ID 000262898000003

    View details for PubMedID 19022739

  • Carboxy-terminal domain of AID required for its mRNA complex formation in vivo PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Nonaka, T., Doi, T., Toyoshima, T., Muramatsu, M., Honjo, T., Kinoshita, K. 2009; 106 (8): 2747-2751

    Abstract

    Activation-induced cytidine deaminase (AID) is essential for the class switch recombination (CSR) and somatic hypermutation (SHM) of Ig genes. Originally, AID was postulated to be an RNA-editing enzyme, because of its structural homology with a known RNA-editing enzyme, APOBEC1. In support of this idea, AID shares many of the properties of RNA-editing enzymes, including nucleocytoplasmic shuttling and a dependency on de novo protein synthesis. However, it has not been shown whether AID recognizes a specific mRNA and edits it to generate an enzyme involved in CSR or SHM. Here, we examined the association between AID and polyadenylated [poly(A)(+)] RNA in vivo, using UV cross-linking coupled with a poly(A) capture method that relies on biotinylated oligo(dT) and streptavidin-conjugated beads. We found that both exogenous AID expressed in transfected CH12 cells and endogenous AID expressed in BL2 cells were associated with poly(A)(+) RNA. Similar protein-poly(A)(+) RNA complexes were formed by APOBEC1 and APOBEC3G. However, the interactions of all of these cytidine deaminase family members, including AID, with poly(A)(+) RNA were indirect. This was expected for APOBEC1, which is known to act through an RNA-interacting cofactor, APOBEC1 complementation factor (ACF). In addition, the carboxy-terminal region of AID, which is essential for class switching, was also required for its interaction with poly(A)(+) RNA. These results suggest that the CSR activity of AID requires an ACF-like cofactor that specifically interacts with the carboxy-terminal domain of AID.

    View details for DOI 10.1073/pnas.0812957106

    View details for Web of Science ID 000263652900051

    View details for PubMedID 19196959

  • The dark side of activation-induced cytidine deaminase: Relationship with leukemia and beyond INTERNATIONAL JOURNAL OF HEMATOLOGY Kinoshita, K., Nonaka, T. 2006; 83 (3): 201-207

    Abstract

    Activation-induced cytidine deaminase (AID) is a unique cellular enzyme that can trigger point mutations and chromosomal translocations, both of which potentially disturb normal cellular metabolism and affect cancer initiation and progression. The involvement of AID in the progression of leukemia has been suggested by multiple groups on the basis of observations of the statistical correlation between AID expression and a poor prognosis of B-cell chronic lymphocytic leukemia. The fact that ectopic expression of AID in mice results in tumors of the lung and T-lymphocytes suggests an oncogenic role for AID. The inducible nature of AID expression indicates that AID might be induced and cause oncogenic mutations, even in epithelial tissues, where AID expression is absent or very weak under normal conditions. If AID can be induced in epithelial cells by inflammatory signals, as from B-lymphocytes, it may be involved in various pathologic conditions, including inflammation-and infection-associated cancers, for which the molecular mechanism is largely unknown, despite the clinical significance of these diseases.

    View details for DOI 10.1532/ijh97.060-11

    View details for Web of Science ID 000237333700007

    View details for PubMedID 16720548

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