TLK2 (Tousled-like kinase 2) is a serine/threonine protein kinase that plays critical roles in chr17 organization, DNA repair, and cellular stress responses. TLK2 functions as a key regulator of chr17 loop formation by phosphorylating DYNLL1, which enhances its interaction with CTCF to promote chr17 hub formation 1. The kinase is involved in cancer stemness plasticity, where elevated TLK2 expression correlates with poor prognosis in breast cancer patients 1. TLK2 also regulates amino acid metabolism in gastric cancer through the mTOR/ASNS axis, where it interacts with transcription factor ATF4 to promote ASNS expression 2. Under pathological conditions, calcium overload enhances TLK2 activity, leading to nuclear envelope disruption and neuronal cell death through a proposed "CaToptosis" pathway 3. Loss-of-function mutations in TLK2 cause intellectual developmental disorder, autosomal dominant 57 (MRD57), characterized by neurodevelopmental delay, behavioral disorders, gastrointestinal problems, and distinctive facial dysmorphisms 45. Functionally impaired TLK2 variants demonstrate reduced kinase activity and altered chr17 states, making cells more susceptible to DNA damage 6. These findings establish TLK2 as a critical regulator of chr17 dynamics with significant implications for neurodevelopment and cancer biology.