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 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

doi:10.1038/cdd.2017.108

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 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^*

^*Corresponding author for this work

10 Citations (Scopus)

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Abstract

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.

Original language	English
Journal	Cell Death and Differentiation
Volume	24
Issue number	11
Pages (from-to)	1872-1885
Number of pages	14
ISSN	1350-9047
DOIs	https://doi.org/10.1038/cdd.2017.108
Publication status	Published - 1 Nov 2017

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Segura-Bayona, S., Knobel, P. A., Gonzalez-Buron, H., Youssef, S. A., Peña-Blanco, A., Coyaud, E., Lopez-Rovira, T., Rein, K., Palenzuela, L., Colombelli, J., Forrow, S., Raught, B., Groth, A., De Bruin, A., & Stracker, T. H. (2017). Differential requirements for Tousled-like kinases 1 and 2 in mammalian development. Cell Death and Differentiation, 24(11), 1872-1885. https://doi.org/10.1038/cdd.2017.108

Segura-Bayona, S, Knobel, PA, Gonzalez-Buron, H, Youssef, SA, Peña-Blanco, A, Coyaud, E, Lopez-Rovira, T, Rein, K, Palenzuela, L, Colombelli, J, Forrow, S, Raught, B, Groth, A, De Bruin, A & Stracker, TH 2017, 'Differential requirements for Tousled-like kinases 1 and 2 in mammalian development', Cell Death and Differentiation, vol. 24, no. 11, pp. 1872-1885. https://doi.org/10.1038/cdd.2017.108

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title = "Differential requirements for Tousled-like kinases 1 and 2 in mammalian development",

abstract = "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.",

author = "Sandra Segura-Bayona and Knobel, {Philip A.} and Helena Gonzalez-Buron and Youssef, {Sameh A.} and Aida Pe{\~n}a-Blanco and Etienne Coyaud and Teresa Lopez-Rovira and Katrin Rein and Llu{\'i}s Palenzuela and Julien Colombelli and Stephen Forrow and Brian Raught and Anja Groth and {De Bruin}, Alain and Stracker, {Travis H.}",

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T1 - Differential requirements for Tousled-like kinases 1 and 2 in mammalian development

AU - Segura-Bayona, Sandra

AU - Knobel, Philip A.

AU - Gonzalez-Buron, Helena

AU - Youssef, Sameh A.

AU - Peña-Blanco, Aida

AU - Coyaud, Etienne

AU - Lopez-Rovira, Teresa

AU - Rein, Katrin

AU - Palenzuela, Lluís

AU - Colombelli, Julien

AU - Forrow, Stephen

AU - Raught, Brian

AU - Groth, Anja

AU - De Bruin, Alain

AU - Stracker, Travis H.

PY - 2017/11/1

Y1 - 2017/11/1

N2 - 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.

AB - 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.

U2 - 10.1038/cdd.2017.108

DO - 10.1038/cdd.2017.108

M3 - Journal article

C2 - 28708136

AN - SCOPUS:85030751604

SN - 1350-9047

VL - 24

SP - 1872

EP - 1885

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

IS - 11

ER -

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

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