The Ku complex: recent advances and emerging roles outside of non-homologous end-joining

Since its discovery in 1981, the Ku complex has been extensively studied under multiple cellular contexts, with most work focusing on Ku in terms of its essential role in non-homologous end-joining (NHEJ). In this process, Ku is well-known as the DNA-binding subunit for DNA-PK, which is central to the NHEJ repair process. However, in addition to the extensive study of Ku's role in DNA repair, Ku has also been implicated in various other cellular processes including transcription, the DNA damage response, DNA replication, telomere maintenance, and has since been studied in multiple contexts, growing into a multidisciplinary point of research across various fields. Some advances have been driven by clarification of Ku's structure, including the original Ku crystal structure and the more recent Ku-DNA-PK_cs crystallography, cryogenic electron microscopy (cryoEM) studies, and the identification of various post-translational modifications. Here, we focus on the advances made in understanding the Ku heterodimer outside of non-homologous end-joining, and across a variety of model organisms. We explore unique structural and functional aspects, detail Ku expression, conservation, and essentiality in different species, discuss the evidence for its involvement in a diverse range of cellular functions, highlight Ku protein interactions and recent work concerning Ku-binding motifs, and finally, we summarize the clinical Ku-related research to date.