Forskning ved Københavns Universitet - Københavns Universitet


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

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

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.
TidsskriftCell Death and Differentiation
Sider (fra-til)1872-1885
Antal sider14
StatusUdgivet - 1 nov. 2017

ID: 185236774