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The Tousled-like kinases regulate genome and epigenome stability: implications in development and disease

  • Sandra Segura-BayonaEmail author
  • Travis H. StrackerEmail author
Review

Abstract

The Tousled-like kinases (TLKs) are an evolutionarily conserved family of serine–threonine kinases that have been implicated in DNA replication, DNA repair, transcription, chromatin structure, viral latency, cell cycle checkpoint control and chromosomal stability in various organisms. The functions of the TLKs appear to depend largely on their ability to regulate the H3/H4 histone chaperone ASF1, although numerous TLK substrates have been proposed. Over the last few years, a clearer picture of TLK function has emerged through the identification of new partners, the definition of specific roles in development and the elucidation of their structural and biochemical properties. In addition, the TLKs have been clearly linked to human disease; both TLK1 and TLK2 are frequently amplified in human cancers and TLK2 mutations have been identified in patients with neurodevelopmental disorders characterized by intellectual disability (ID), autism spectrum disorder (ASD) and microcephaly. A better understanding of the substrates, regulation and diverse roles of the TLKs is needed to understand their functions in neurodevelopment and determine if they are viable targets for cancer therapy. In this review, we will summarize current knowledge of TLK biology and its potential implications in development and disease.

Keywords

Kinase Histone chaperone TLK1 TLK2 ASF1A ASF1B DNA replication DNA repair Genome instability Epigenetics Cancer Cell cycle checkpoint Neurodevelopmental disorder 

Notes

Acknowledgements

We are grateful to members of the Stracker lab and A. Groth for discussions of unpublished data and suggestions. We apologize to those colleagues whose relevant work could not be specifically mentioned due to space constraints.

Funding

THS was funded by the Spanish Ministry of Science, Innovation and Universities (BFU2015-68354/GENPATH, PGC2018-095616-B-100/GINDATA and FEDER, the Centres of Excellence Severo Ochoa award and the CERCA Programme. SSB was funded by a PhD fellowship and the project LCF/PR/GN14/10270002 from the “la Caixa” Foundation.

Compliance with ethical standards

Conflict of interest

The authors declare no competing interests.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of OncologyInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and TechnologyBarcelonaSpain
  2. 2.The Francis Crick InstituteLondonUK

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