Aging is an intricate process that is characterized by multiple hallmarks including stem cell exhaustion, genome instability, epigenome alteration, impaired proteostasis, and cellular senescence. While each of these 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, results in cellular senescence with persistent DNA double-strand breaks and elevation of histone H2A mono- and poly-ubiquitination (H2Aub). The high H2Aub initiates proteasome-dependent histone proteolysis, leading to global epigenetic alteration, ubiquitinated protein accumulation, and senescence reinforcement. When these defects occur in mice carrying Brap deletions in cerebral cortical neural progenitors or postnatal neurons, they accelerate brain aging, induce neurodegeneration, and shorten lifespan. As we show H2Aub is also increased in human brain tissues of Alzheimer disease, these data together suggest that chromatin aberrations mediated by H2Aub act as a nexus of multiple aging hallmarks.

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