BRPF1-KAT6A/KAT6B Complex: Molecular Structure, Biological Function and Human Disease.

Abstract

Simple SummaryBRPF1 (also named as BR140) was identified 28 years ago, and it was not until the past 5 years that its mutations in humans caught increasing attention. Those patients with BRPF1 mutations often display intellectual disability or suffer from leukemia or medulloblastoma. BRPF1 is an activator and a scaffold protein of a multiunit complex, with other members being KAT6A/KAT6B, ING5 or ING4 and MEAF6. This review summarizes the molecular structure, biological function and human diseases associated with the BRPF1-KAT6A/KAT6B complex and summarizes the development of inhibitors for targeting specific domains of BRPF1.The bromodomain and PHD finger–containing protein1 (BRPF1) is a member of family IV of the bromodomain-containing proteins that participate in the post-translational modification of histones. It functions in the form of a tetrameric complex with a monocytic leukemia zinc finger protein (MOZ or KAT6A), MOZ-related factor (MORF or KAT6B) or HAT bound to ORC1 (HBO1 or KAT7) and two small non-catalytic proteins, the inhibitor of growth 5 (ING5) or the paralog ING4 and MYST/Esa1-associated factor 6 (MEAF6). Mounting studies have demonstrated that all the four core subunits play crucial roles in different biological processes across diverse species, such as embryonic development, forebrain development, skeletal patterning and hematopoiesis. BRPF1, KAT6A and KAT6B mutations were identified as the cause of neurodevelopmental disorders, leukemia, medulloblastoma and other types of cancer, with germline mutations associated with neurodevelopmental disorders displaying intellectual disability, and somatic variants associated with leukemia, medulloblastoma and other cancers. In this paper, we depict the molecular structures and biological functions of the BRPF1-KAT6A/KAT6B complex, summarize the variants of the complex related to neurodevelopmental disorders and cancers and discuss future research directions and therapeutic potentials.