Tousled-like kinases phosphorylate Asf1 to promote histone supply during DNA replication

Ilnaz M. Klimovskaia, Clifford Young, Caroline B. Strømme, Patrice Menard, Zuzana Jasencakova, Jakob Mejlvang, Katrine Ask, Michael Ploug, Michael L. Nielsen, Ole N. Jensen and Anja Groth ()
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Ilnaz M. Klimovskaia: Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen, Ole Maaløes Vej 5
Clifford Young: University of Southern Denmark, Campusvej 55
Caroline B. Strømme: Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen, Ole Maaløes Vej 5
Patrice Menard: Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen, Ole Maaløes Vej 5
Zuzana Jasencakova: Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen, Ole Maaløes Vej 5
Jakob Mejlvang: Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen, Ole Maaløes Vej 5
Katrine Ask: Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen, Ole Maaløes Vej 5
Michael Ploug: The Finsen Laboratory, Rigshospitalet, Copenhagen Biocenter, Ole Maaløes Vej 5
Michael L. Nielsen: The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Blegdamsvej 3B
Ole N. Jensen: University of Southern Denmark, Campusvej 55
Anja Groth: Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen, Ole Maaløes Vej 5

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract During DNA replication, nucleosomes are rapidly assembled on newly synthesized DNA to restore chromatin organization. Asf1, a key histone H3-H4 chaperone required for this process, is phosphorylated by Tousled-like kinases (TLKs). Here, we identify TLK phosphorylation sites by mass spectrometry and dissect how phosphorylation has an impact on human Asf1 function. The divergent C-terminal tail of Asf1a is phosphorylated at several sites, and this is required for timely progression through S phase. Consistent with this, biochemical analysis of wild-type and phospho-mimetic Asf1a shows that phosphorylation enhances binding to histones and the downstream chaperones CAF-1 and HIRA. Moreover, we find that TLK phosphorylation of Asf1a is induced in cells experiencing deficiency of new histones and that TLK interaction with Asf1a involves its histone-binding pocket. We thus propose that TLK signalling promotes histone supply in S phase by targeting histone-free Asf1 and stimulating its ability to shuttle histones to sites of chromatin assembly.

Date: 2014
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DOI: 10.1038/ncomms4394

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