KMT5B is a histone methyltransferase that catalyzes methylation of histone H4 lysine 20, specifically converting H4K20me1 to H4K20me2 and H4K20me2 to H4K20me3 1. The resulting H4K20me3 mark functions as an epigenetic tag for transcriptional repression, particularly in pericentric heterochromatin where KMT5B establishes constitutive heterochromatin 2. KMT5B facilitates TP53BP1 recruitment and DNA repair through non-homologous end-joining by catalyzing H4K20 methylation 1. Beyond DNA repair, KMT5B regulates neuronal development and myogenesis 3. KMT5B localizes to mitotic spindle microtubules, linking it to cellular proliferation biology 4. Pathogenic KMT5B variants cause neurodevelopmental disorder characterized by global developmental delay, macrocephaly, autism spectrum disorder, hypotonia, and congenital heart defects 56. Loss of KMT5B function impairs neuronal dendritic complexity and accelerates neural progenitor cell migration 6. In cancer, KMT5B overexpression mediates H4K20me3-dependent silencing of inflammatory genes in persister cells, promoting drug tolerance 7, while mutant p53 upregulates KMT5B to confer chemoresistance in nasopharyngeal carcinoma 8.