Tousled-Like Kinase Function in DNA Replication and Repair

Tousled-like kinases (TLKs) are conserved serine/threonine kinases that orchestrate chromatin dynamics during DNA replication and repair. These enzymes transiently associate with histone chaperones and DNA repair factors to ensure timely nucleosome assembly behind replication forks and facilitate efficient response to genotoxic stress. In unperturbed S phase, TLK activity promotes phosphorylation of histone H3 and the histone chaperone ASF1, driving chromatin reassembly and stabilising replication forks. Upon DNA damage, checkpoint kinases inhibit TLK activity to sustain cell cycle arrest and allow recruitment of repair complexes. TLKs later re-activate to phosphorylate effectors such as Rad9, a subunit of the 9-1-1 clamp, coordinating checkpoint termination and resumption of the cell cycle once repair is complete. Beyond checkpoint control, TLKs directly influence processing of double-strand breaks (DSBs) by modulating factors in homologous recombination repair (HRR) and non-homologous end-joining (NHEJ). Dysregulation of TLK function has been linked to genomic instability, neurodevelopmental disorders and tumour progression, making these kinases promising targets for therapeutic intervention.

Research from Nature Portfolio

Structural insights into TLK regulation have been advanced through determination of the kinase domain crystal structure of TLK2. This work revealed a coiled-coil mediated dimerisation interface essential for ordered autophosphorylation and higher-order oligomer formation, shedding light on how TLKs switch between inactive and active states. Mapping of patient-associated mutations further demonstrated that perturbation of this oligomerisation impairs kinase activity, offering a framework for targeted inhibitor design. Complementing structural studies, high-yield expression systems for human TLK1B have been developed, yielding dephosphorylated, active enzyme at scale. This approach enables detailed biochemical and biophysical characterisation of TLK–substrate interactions and supports structure-based discovery of TLK inhibitors. Together, these advances establish a molecular platform for rational drug development directed at TLK-mediated pathways in DNA replication and repair.

Tousled-Like Kinase Function in DNA Replication and Repair publication trend

The graph below shows the total number of articles in tousled-like kinase function in dna replication and repair across all publications each year (not limited to Nature Index journals).

Technical terms

Tousled-like kinase (TLK): A family of serine/threonine kinases that regulate chromatin assembly and DNA repair.

Double-strand break (DSB): A form of DNA damage in which both strands of the DNA helix are severed.

Homologous recombination repair (HRR): An accurate DSB repair pathway that uses a sister chromatid as a template.

Non-homologous end-joining (NHEJ): A DSB repair mechanism that ligates DNA ends directly without a homologous template.

Histone chaperone ASF1: A protein that binds histones H3/H4 and facilitates their deposition onto DNA during replication and repair.

Autophosphorylation: A process by which a kinase phosphorylates itself to modulate its own activity.

9-1-1 complex: A heterotrimeric clamp (Rad9-Rad1-Hus1) that senses DNA damage and activates checkpoint signalling.

References

1. Untousling the Role of Tousled-like Kinase 1 in DNA Damage Repair. International Journal of Molecular Sciences (2023).
2. Exploiting TLK1 and Cisplatin Synergy for Synthetic Lethality in Androgen-Insensitive Prostate Cancer. Biomedicines (2023).
3. Molecular basis of Tousled-Like Kinase 2 activation. Nature Communications (2018).
4. Tousled-Like Kinase-Dependent Phosphorylation of Rad9 Plays a Role in Cell Cycle Progression and G2/M Checkpoint Exit. PLOS ONE (2013).
5. Phosphorylation-Mediated Control of Histone Chaperone ASF1 Levels by Tousled-Like Kinases. PLOS ONE (2009).
6. High yield bacterial expression, purification and characterisation of bioactive Human Tousled-like Kinase 1B involved in cancer. Scientific Reports (2018).
7. TLK1B mediated phosphorylation of Rad9 regulates its nuclear/cytoplasmic localization and cell cycle checkpoint. BMC Molecular and Cell Biology (2016).