TLK2

TLK2 (Tousled-like kinase 2) is a nuclear serine/threonine kinase that supports chromatin assembly, DNA replication, and genome stability through regulation of histone management pathways and chromatin-associated factors^[1][2][3]. Mechanistically, TLK2 phosphorylates ASF1 family histone chaperones and promotes histone supply and nucleosome assembly, thereby coupling chromatin restoration to DNA synthesis and maintenance of replication fork integrity^[1][4][5]. During the DNA damage response, TLK2 regulates ASF1A-dependent chromatin reassembly at damaged loci and is required for efficient recovery from G2 checkpoint arrest, linking chromatin restoration to cell-cycle re-entry after genotoxic stress^[2]. In disease contexts, aberrant TLK2 activity has been associated with tumor progression, and genomic analyses identified recurrent TLK2 amplification in a subset of estrogen receptor-positive breast cancers where elevated expression correlates with aggressive clinical behavior and poor outcome^[6]. Structural studies further demonstrate that TLK2 activation depends on coiled-coil-mediated dimerization and ordered autophosphorylation, providing a mechanistic framework for kinase regulation and therapeutic targeting^[3]. Compared with the closely related isoform TLK1, which shares extensive kinase-domain homology and overlapping substrates, TLK2 exhibits distinct functions during recovery from DNA damage despite substantial functional overlap under unperturbed conditions^[7]. For experimental applications, TLK2 inhibition suppresses growth of TLK2-high cancer models, and structural characterization has enabled evaluation of small-molecule inhibitor binding and rational inhibitor-development strategies^[3][6].