Differential requirements for Tousled-like kinases 1 and 2 in mammalian development

Sandra Segura-Bayona, Philip A. Knobel, Helena Gonzalez-Buron, Sameh A. Youssef, Aida Pena-Blanco, Etienne Coyaud, Teresa Lopez-Rovira, Katrin Rein, Lluis Palenzuela, Julien Colombelli, Stephen Forrow, Brian Raught, Anja Groth, Alain de Bruin, Travis H. Stracker*

*Bijbehorende auteur voor dit werk

    OnderzoeksoutputAcademicpeer review

    10 Citaten (Scopus)

    Samenvatting

    The regulation of chromatin structure is critical for a wide range of essential cellular processes. The Tousled-like kinases, TLK1 and TLK2, regulate ASF1, a histone H3/H4 chaperone, and likely other substrates, and their activity has been implicated in transcription, DNA replication, DNA repair, RNA interference, cell cycle progression, viral latency, chromosome segregation and mitosis. However, little is known about the functions of TLK activity in vivo or the relative functions of the highly similar TLK1 and TLK2 in any cell type. To begin to address this, we have generated Tlk1- and Tlk2-deficient mice. We found that while TLK1 was dispensable for murine viability, TLK2 loss led to late embryonic lethality because of placental failure. TLK2 was required for normal trophoblast differentiation and the phosphorylation of ASF1 was reduced in placentas lacking TLK2. Conditional bypass of the placental phenotype allowed the generation of apparently healthy Tlk2-deficient mice, while only the depletion of both TLK1 and TLK2 led to extensive genomic instability, indicating that both activities contribute to genome maintenance. Our data identifies a specific role for TLK2 in placental function during mammalian development and suggests that TLK1 and TLK2 have largely redundant roles in genome maintenance.

    Originele taal-2English
    Pagina's (van-tot)1872-1885
    Aantal pagina's14
    TijdschriftCell death and differentiation
    Volume24
    Nummer van het tijdschrift11
    DOI's
    StatusPublished - nov-2017

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