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Human Molecular Genetics, 2000, Vol. 9, No. 12 1795-1803
© 2000 Oxford University Press

Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B

Guang-hui Wang1,2, Noriko Sawai1, Svetlana Kotliarova1, Ichiro Kanazawa2 and Nobuyuki Nukina1,+

1Laboratory for CAG Repeat Diseases, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan and 2Department of Neurology, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113, Japan

Machado–Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder caused by an expansion of the polyglutamine tract near the C-terminus of the MJD1 gene product, ataxin-3. The mutant ataxin-3 forms intranuclear inclusions in cultured cells as well as in diseased human brain and also causes cell death in transfected cells. However, the normal function of ataxin-3 remains unknown. To explore the function of ataxin-3, we used the two-hybrid system to screen for the protein(s) that interacts with ataxin-3. We found that ataxin-3 interacts with two human homologs of the yeast DNA repair protein RAD23, HHR23A and HHR23B. Furthermore, we confirmed that ataxin-3 interacts with the ­ubiquitin-like domain at the N-terminus of the HHR23 proteins, which is important for nucleotide excision repair; however, ataxin-3 does not interact with ­ubiquitin, implying that ataxin-3 might be functionally associated with the HHR23 proteins through this specific interaction. The normal and mutant ataxin-3 proteins show no difference in their ability to bind to the HHR23 proteins. However, in 293 cells HHR23A is recruited to intranuclear inclusions formed by the mutant ataxin-3 through its interaction with ataxin-3. These results suggest that this interaction is associated with the normal function of ataxin-3 and that some functional abnormality of the HHR23 proteins might exist in MJD.

+ To whom correspondence should be addressed. Tel: +81 48 467 9702; Fax: +81 48 462 4796; Email: nukina@brain.riken.go.jp


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