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Molecular and Cellular Biology, April 2008, p. 2690-2700, Vol. 28, No. 8
0270-7306/08/$08.00+0     doi:10.1128/MCB.01983-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Human Rvb1/Tip49 Is Required for the Histone Acetyltransferase Activity of Tip60/NuA4 and for the Downregulation of Phosphorylation on H2AX after DNA Damage{triangledown} ,{dagger}

Sudhakar Jha, Etsuko Shibata, and Anindya Dutta*

Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Jordan 1240, 1300 Jefferson Park Avenue, Charlottesville, Virginia 22908

Received 3 November 2007/ Returned for modification 26 November 2007/ Accepted 6 February 2008

The role of chromatin-remodeling factors in transcription is well established, but the link between chromatin-remodeling complexes and DNA repair remains unexplored. Human Rvb1 and Rvb2 are highly conserved AAA+ ATP binding proteins that are part of various chromatin-remodeling complexes, such as Ino80, SNF2-related CBP activator protein (SRCAP), and Tip60/NuA4 complexes, but their molecular function is unclear. The depletion of Rvb1 increases the amount and persistence of phosphorylation on chromatin-associated H2AX after the exposure of cells to UV irradiation or to mitomycin C, cisplatin, camptothecin, or etoposide, without increasing the amount of DNA damage. Tip60 depletion, but not Ino80 or SRCAP depletion, mimics the effect of Rvb1 depletion on H2AX phosphorylation. Rvb1 is required for the histone acetyltransferase (HAT) activity of the Tip60 complex, and histone H4 acetylation is required prior to the dephosphorylation of phospho-H2AX. Thus, Rvb1 is critical for the dephosphorylation of phospho-H2AX due to the role of Rvb1 in maintaining the HAT activity of Tip60/NuA4, implicating the Rvb1-Tip60 complex in the chromatin-remodeling response of cells after DNA damage.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Jordan 1240, 1300 Jefferson Park Ave., Charlottesville, VA 22908. Phone: (434) 924-1227. Fax: (434) 924-5069. E-mail: ad8q{at}virginia.edu

{triangledown} Published ahead of print on 19 February 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, April 2008, p. 2690-2700, Vol. 28, No. 8
0270-7306/08/$08.00+0     doi:10.1128/MCB.01983-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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