Cells respond to DNA damage by recruiting various DNA Damage Response (DDR) proteins to the site of damage. One of the key regulators of this DDR pathway is TIP60 complex (TIP60.com) (Jha S. et. al Mol Cell. 2009, 34:521-33). TIP60.com is a tumor suppressor and known to be down-regulated in multiple cancers, including Human papillomavirus (HPV) induced cancer (Jha S. et. al Mol Cell. 2010, 38:700-11). In this study we have identified cellular regulators of TIP60.com. RVB1/RVB2 (RuvBL1/RuvBL2 or Pontin/Reptin) are enigmatic AAA+ ATPase proteins that are present in multiple cellular complexes. Although they have been implicated in many cellular functions, the exact molecular function of RVB proteins in the various complexes is not clear. We had shown earlier that RVBs are required for optimal lysine acetyltransferase activity of TIP60.com but not of the pure recombinant TIP60 polypeptide (Jha S. et. al Mol Cell Biol 2008, 28:2690-700). In this study we identify two molecular functions of RVBs in TIP60.com. First, RVBs negate the repression of catalytic activity of TIP60 by another protein in TIP60.com, p400. RVBs competitively displace the SNF2 domain of p400 from the TIP60 polypeptide. In addition RVBs are also required for heat stability of TIP60.com by a p400- independent pathway. Thus RVB proteins act as molecular adaptors that facilitate the optimal assembly, heat-stability and function of the TIP60 complex.
Sudhakar Jha1*$, Ashish Gupta1*, Ashraf Dar1 and Anindya Dutta1#
1Department of Biochemistry and Molecular Genetics, University of Virginia, School of Medicine, 1240 Jordan, 1340 Jefferson Park Ave, Charlottesville, VA 22908, USA
$Present address: Cancer Science Institute of Singapore and Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
* SJ and AG contributed equally to this work