Surprising complexity of the Asf1 histone chaperone-Rad53 kinase interaction

Yue Jiao 1 Karsten Seeger 1 Aurelie Lautrette 2 Albane Gaubert 2 Florence Mousson 2 Raphael Guérois 3 Carl Mann 1, * Françoise Ochsenbein 2, *
* Corresponding author
1 LBI - Laboratoire de Biologie Intégrative
2 LBSR - Laboratoire de Biologie Structurale et Radiobiologie
3 IBITECS - Institut de Biologie et de Technologies de Saclay
Abstract : The histone chaperone Asf1 and the checkpoint kinase Rad53 are found in a complex in budding yeast cells in the absence of genotoxic stress. Our data suggest that this complex involves at least three interaction sites. One site involves the H3-binding surface of Asf11 with an as yet undefined surface of Rad53. A second site is formed by the Rad53-FHA1 domain binding to Asf1-$T_{270}$ phosphorylated by casein kinase II. The third site involves the C-terminal 21 amino acids of Rad53 bound to the conserved Asf1 N-terminal domain. The structure of this site showed that the Rad53 C-terminus binds Asf1 in a remarkably similar manner to peptides derived from the histone cochaperones HirA and CAF-I. We call this binding motif, $(R/K)R(I/A/V)$x$(L/P)$, the AIP box for Asf1-Interacting Protein box. Furthermore, C-terminal Rad53-$F_{820}$ binds the same pocket of Asf1 as does histone $H4-F_{100}$. Thus Rad53 competes with histones H3-H4 and cochaperones HirA/CAF-I for binding to Asf1. Rad53 is phosphorylated and activated upon genotoxic stress. The Asf1-Rad53 complex dissociated when cells were treated with hydroxyurea but not methyl-methane-sulfonate, suggesting a regulation of the complex as a function of the stress. We identified a rad53 mutation that destabilized the Asf1-Rad53 complex and increased the viability of rad9 and rad24 mutants in conditions of genotoxic stress, suggesting that complex stability impacts the DNA damage response.
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Submitted on : Tuesday, March 27, 2018 - 2:44:31 PM
Last modification on : Thursday, February 7, 2019 - 2:29:29 PM

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Yue Jiao, Karsten Seeger, Aurelie Lautrette, Albane Gaubert, Florence Mousson, et al.. Surprising complexity of the Asf1 histone chaperone-Rad53 kinase interaction. Proceedings of the National Academy of Sciences of the United States of America , National Academy of Sciences, 2012, 109, pp.2866 - 2871. ⟨10.1073/pnas.1106023109⟩. ⟨cea-01744552⟩

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