HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 24, 17387-17394, June 15, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/24/17387    most recent M611849200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Masuda, K. Articles by O-Wang, J. Search for Related Content PubMed PubMed Citation Articles by Masuda, K. Articles by O-Wang, J. Social Bookmarking                      What's this?

DNA Polymerases and Function in the Same Genetic Pathway to Generate Mutations at A/T during Somatic Hypermutation of Ig Genes^*

Keiji Masuda, Rika Ouchida, Masaki Hikida, Tomohiro Kurosaki, Masayuki Yokoi^¶, Chikahide Masutani^¶, Mineaki Seki^||, Richard D. Wood^||, Fumio Hanaoka^¶, and Jiyang O-Wang¹

From the Laboratories for Immune Diversity and Lymphocyte Differentiation, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama 230-0045, Japan, the ^¶Graduate School of Frontier Biosciences, Osaka University, and SORST, Japan Science and Technology Agency, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan, and the ^||University of Pittsburgh Cancer Institute, Hillman Cancer Center, Research Pavilion, Pittsburgh, Pennsylvania 15213

Somatic hypermutation of the Ig genes requires the activity of multiple DNA polymerases to ultimately introduce mutations at both A/T and C/G base pairs. Mice deficient for DNA polymerase (POLH) exhibited an 80% reduction of the mutations at A/T, whereas absence of polymerase (POLQ) resulted in 20% reduction of both A/T and C/G mutations. To investigate whether the residual A/T mutations observed in the absence of POLH are generated by POLQ and how these two polymerases might cooperate or compete with each other to generate A/T mutations, here we have established mice deficient for both POLH and POLQ. Polq^–/–Polh^–/– mice, however, did not show a further decrease of A/T mutations as compared with Polh^–/– mice, suggesting that POLH and POLQ function in the same genetic pathway in the generation of these mutations. Frequent misincorporation of nucleotides, in particular opposite template T, is a known feature of POLH, but the efficiency of extension beyond the misincorporation differs significantly depending on the nature of the mispairing. Remarkably, we found that POLQ catalyzed extension more efficiently than POLH from all types of mispaired termini opposite A or T. Moreover, POLQ was able to extend mispaired termini generated by POLH albeit at a relatively low efficiency. These results reveal genetic and biochemical interactions between POLH and POLQ and suggest that POLQ might cooperate with POLH to generate some of the A/T mutations during the somatic hypermutation of Ig genes.

Received for publication, December 27, 2006 , and in revised form, April 10, 2007.

^* This work was supported in part by Grant-in-aid for Scientific Research on Priority Areas 17047047 from the Ministry of Education, Culture, Sports, Science, and Technology in Japan and by National Institutes of Health Grant CA101980 (to R. D. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1 and Tables S1–S4.

¹ To whom correspondence should be addressed: Laboratory for Immune Diversity, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama 230-0045, Japan. Tel.: 81-45-503-7041; Fax: 81-45-503-7040; E-mail: oh{at}rcai.riken.jp.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				R. Prasad, M. J. Longley, F. S. Sharief, E. W. Hou, W. C. Copeland, and S. H. Wilson Human DNA polymerase {theta} possesses 5'-dRP lyase activity and functions in single-nucleotide base excision repair in vitro Nucleic Acids Res., April 1, 2009; 37(6): 1868 - 1877. [Abstract] [Full Text] [PDF]

				H. Saribasak, D. Rajagopal, R. W Maul, and P. J Gearhart Hijacked DNA repair proteins and unchained DNA polymerases Phil Trans R Soc B, March 12, 2009; 364(1517): 605 - 611. [Abstract] [Full Text] [PDF]

				A. Ukai, K. Ishimaru, R. Ouchida, H. Mori, C. Kano, T. Moritan, and J.-Y. Wang Induction of A:T Mutations Is Dependent on Cellular Environment but Independent of Mutation Frequency and Target Gene Location J. Immunol., December 1, 2008; 181(11): 7835 - 7842. [Abstract] [Full Text] [PDF]

				P. Pham, K. Zhang, and M. F. Goodman Hypermutation at A/T Sites during G{middle dot}U Mismatch Repair in Vitro by Human B-cell Lysates J. Biol. Chem., November 14, 2008; 283(46): 31754 - 31762. [Abstract] [Full Text] [PDF]

				S. Roa, E. Avdievich, J. U. Peled, T. MacCarthy, U. Werling, F. L. Kuang, R. Kan, C. Zhao, A. Bergman, P. E. Cohen, et al. Ubiquitylated PCNA plays a role in somatic hypermutation and class-switch recombination and is required for meiotic progression PNAS, October 21, 2008; 105(42): 16248 - 16253. [Abstract] [Full Text] [PDF]

				N. S. Longo, C. L. Satorius, A. Plebani, A. Durandy, and P. E. Lipsky Characterization of Ig Gene Somatic Hypermutation in the Absence of Activation-Induced Cytidine Deaminase J. Immunol., July 15, 2008; 181(2): 1299 - 1306. [Abstract] [Full Text] [PDF]

				M. E. Arana, M. Seki, R. D. Wood, I. B. Rogozin, and T. A. Kunkel Low-fidelity DNA synthesis by human DNA polymerase theta Nucleic Acids Res., June 1, 2008; 36(11): 3847 - 3856. [Abstract] [Full Text] [PDF]

				R. A. Busuttil, Q. Lin, P. J. Stambrook, R. Kucherlapati, and J. Vijg Mutation Frequencies and Spectra in DNA Polymerase {eta}-Deficient Mice Cancer Res., April 1, 2008; 68(7): 2081 - 2084. [Abstract] [Full Text] [PDF]