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Reputable Mentor II
Reputable Mentor II
Klimovskaia IM, Young C, Strømme CB, Menard P, Jasencakova Z, Mejlvang J, Ask K, Ploug M, Nielsen ML, Jensen ON, Groth A.
Nat Commun. 2014 Mar 6;5:3394. doi: 10.1038/ncomms4394.
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.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3977046/
University of Copenhagen, University of Southern Denmark, Copenhagen Biocenter
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