{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTLK2 overexpression and amplification have been linked to aggressive cancer phenotypes. In estrogen receptor–positive breast cancer, increased TLK2 levels correlate with enhanced cell cycle progression, impaired DNA damage checkpoint signaling, and subsequent chromosomal instability, ultimately rendering tumors more resistant to therapy. In glioblastoma, TLK2 overexpression drives malignancy by modulating SRC signaling to promote cell growth, migration, invasion, and epithelial–mesenchymal transition, while in acute myeloid leukemia its expression—regulated by miR‑21—further influences proliferation and apoptotic responses. Moreover, TLK2’s deregulation contributes to altered chromatin organization that can favor immune evasion in chromosomally unstable cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA critical aspect of TLK2 function lies in its regulation of chromatin assembly and the DNA damage response. TLK2 phosphorylates histone H3–H4 chaperones (ASF1a and ASF1b) to prevent their degradation and to promote efficient replication‐coupled nucleosome assembly. In response to DNA damage, TLK2 facilitates the restoration of chromatin structure by regulating Asf1A, ensuring proper histone H3 incorporation and enabling timely checkpoint recovery. In addition, interactions between TLK2, ASF1, and DNA repair factors such as Rad9 underscore its fundamental role in maintaining genome stability."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "9"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in cancer and DNA repair, TLK2 is pivotal in other cellular contexts. It functions as a cellular repressor of gammaherpesvirus reactivation, maintaining viral latency by limiting the expression of lytic proteins. Furthermore, de novo and inherited heterozygous mutations in TLK2 have been associated with a distinct neurodevelopmental syndrome characterized by intellectual disability, behavioral abnormalities, and dysmorphic features. Structural studies have shed light on the mechanisms regulating TLK2 activity, with mutations affecting its kinase function underlying neurodevelopmental disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "13"}]}, {"type": "t", "text": ""}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jin-Ah Kim, Meenakshi Anurag, Jamunarani Veeraraghavan, et al. 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