Human Rvb1/Tip49 is required for the HAT activity of TIP60/NuA4 and for the downregulation of phosphorylation on H2AX after DNA damage

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

^* To whom correspondence should be addressed. Email: ad8q{at}virginia.edu.

	Abstract

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/Rvb2 are highly conserved AAA+ ATP binding proteins that are part of various chromatin-remodeling complexes such as Ino80, SRCAP and Tip60/NuA4, but their molecular function is unclear. Depletion of Rvb1 increases the amount and persistence of phosphorylation on chromatin-associated H2AX after 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 H4 acetyl transferase activity of the Tip60 complex and histone H4 acetylation is required prior to the dephosphorylation of phosphoH2AX. Thus Rvb1 is critical for the dephosphorylation of phosphoH2AX due to its role in maintaining the HAT activity of Tip60/NuA4, implicating the Rvb1-Tip60 complex in the chromatin-remodeling response of cells after DNA damage.