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

Ilnaz M Kamalyukova, Clifford Young, Caroline B Strømme, Patrice Menard, Zusana Jasencakova, Jakob Mejlvang, Katrine Ask, Michael Ploug, Michael L Nielsen, Ole N Jensen, Anja Groth

Research output: Contribution to journalJournal articleResearchpeer-review

55 Citations (Scopus)

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.
Original languageEnglish
JournalNature Communications
Volume5
Pages (from-to)3394
ISSN2041-1723
DOIs
Publication statusPublished - 2014

Cite this