摘要：SummaryAging is an intricate process characterized by multiple hallmarks including stem cell exhaustion, genome instability, epigenome alteration, impaired proteostasis, and cellular senescence. Whereas each of these traits is detrimental at the cellular level, it remains unclear how they are interconnected to cause systemic organ deterioration. Here we show that abrogating Brap, a BRCA1-associated protein essential for neurogenesis, results in persistent DNA double-strand breaks and elevation of histone H2A mono- and poly-ubiquitination (H2Aub). These defects extend to cellular senescence and proteasome-mediated histone H2A proteolysis with alterations in cells’ proteomic and epigenetic states. Brap deletion in the mouse brain causes neuroinflammation, impaired proteostasis, accelerated neurodegeneration, and substantially shortened the lifespan. We further show the elevation of H2Aub also occurs in human brain tissues with Alzheimer’s disease. These data together suggest that chromatin aberrations mediated by H2Aub may act as a nexus of multiple aging hallmarks and promote tissue-wide degeneration.Graphical abstractDisplay OmittedHighlights•Losing BRCA1-associated Brap Results in Sustained DNA Damage and Cellular Senescence•Brap Deficient Cells and Brain Show a Hallmark Increase in Histone H2A Ubiquitination•Transcriptome and Proteome altered by Brap Mediate Neuroinflammation and Proteopathy•Elevated Ubiquityl-H2A is associated with Neurodegeneration and Alzheimer’s DiseaseBiological sciences; Neuroscience; Cellular neuroscience; Cell biology; Functional aspects of cell biology
