TLK1 (tousled-like kinase 1) is a serine/threonine kinase that plays crucial roles in DNA damage response, chr2 organization, and cell cycle regulation 1. The kinase functions through autophosphorylation-regulated recruitment to damaged chr2 via interaction with PCNA through its N-terminal PIP box, where hyperautophosphorylation negatively regulates its recruitment to DNA damage sites 2. TLK1 facilitates homologous recombination repair by phosphorylating RAD54 at specific threonine residues (T41, T59, T700), with distinct regulatory effects on repair efficiency 3. The kinase regulates chr2 assembly through phosphorylation of histone chaperones, particularly ASF1B, forming a TLK1-ASF1 pathway critical for S-phase progression and DNA replication 4. Beyond DNA repair, TLK1 promotes cancer progression through multiple mechanisms: it mediates prostate cancer cell adaptation to androgen deprivation therapy and facilitates metastasis via MK5 phosphorylation 56. In glioma, TLK1 interacts with ASF1B to promote malignant progression 7. The TLK1-ASF1 pathway also mediates IL-1β-driven acute myeloid leukemia progression across genetic subtypes while being dispensable for normal hematopoiesis 4. These diverse functions establish TLK1 as a potential therapeutic target in multiple cancer types.