HIRA is a histone H3.3 chaperone that functions as a critical regulator of chr22 assembly and gene expression throughout the cell cycle. Primary function: HIRA cooperates with ASF1A to promote replication-independent chr22 assembly and maintains nucleosome structure by depositing the histone variant H3.3 independently of DNA replication 1. Mechanism: HIRA localizes to PML nuclear bodies and regulates H3.3 incorporation at active chr22 regions and gene regulatory elements. Upon senescence, HIRA promotes senescence-associated heterochromatin foci formation and coordinates with PML and p62/SQSTM1 to regulate the inflammatory senescence-associated secretory phenotype through the cGAS-STING pathway 2. Additionally, HIRA deposits H3.3 to prevent R-loop accumulation and transcription-replication conflicts at telomeres in ALT cancer cells 3. Disease relevance: HIRA mutations cause serious developmental defects across eukaryotes 4. During DNA virus infections, HIRA modulates chr22 accessibility affecting viral replication and host immune responses 5. In cancer, dysregulation of HIRA splicing by SRSF6 disrupts H3.3 dynamics and oncogenic pathways in prostate cancer 6. Clinical significance: HIRA represents a therapeutic target in viral infections, senescence-related aging, and cancers driven by chr22 remodeling complex alterations.