Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres

During replicative aging of primary cells morphological transformations occur, the expression pattern is altered and chromatin changes globally. Here we show that chronic damage signals, likely caused by telomere processing, impact expression of histones and lead to their depletion. Interrogation of the abundance and cell cycle expression of histones and histone chaperones revealed defects in histone biosynthesis during replicative aging. Simultaneously, epigenetic marks were redistributed across the phases of the cell cycle and the DNA damage response (DDR) machinery was activated. The age-dependent reprogramming affected telomeric chromatin itself, which was progressively destabilized, resulting in a boost of the telomere associated DDR signal with each successive cell cycle. We propose a mechanism where changes in the structural and epigenetic integrity of telomeres impact core histones and their chaperones, enforcing a self-perpetuating pathway of global epigenetic changes that ultimately leads to senescence.