Beyond Nucleosome Assembly - Chromatin Assembly Factor 1 as a Nexus of Genome Stability Cell Identity and Cancer

Abstract

Chromatin assembly factor 1 (CAF-1) is an evolutionarily conserved histone chaperone complex that deposits newly synthesized histones H3-H4 onto nascent DNA. By coupling DNA synthesis to nucleosome assembly, CAF-1 restores chromatin after replication and repair, supports epigenetic inheritance, and helps maintain cellular identity. Its biological role, however, extends beyond chromatin packaging. Structural and functional studies now place CAF-1 at the intersection of replication-fork progression, replication-stress tolerance, DNA damage repair, translesion synthesis, R-loop control, lineage-specific transcription, and innate immune regulation. These functions are especially relevant in cancer, where rapid proliferation is accompanied by persistent replication stress, genome instability, and selection for epigenetic states that favor survival and plasticity.

Aberrant expression of the CAF-1 subunits CHAF1A and CHAF1B has been reported across solid and hematologic malignancies and is frequently associated with aggressive clinicopathologic features, treatment resistance, or poor outcome. Mechanistically, cancer cells may exploit CAF-1 to preserve fork fitness, facilitate DNA repair and lesion bypass, stabilize oncogenic chromatin states, restrict differentiation, and silence endogenous retroelements that would otherwise activate antiviral signaling. Recent studies linking CHAF1A to RAD51 loading, RAD18-dependent damage tolerance, and suppression of ERV-driven type I interferon responses illustrate how a canonical histone chaperone can influence both therapeutic resistance and tumor immunity. This review summarizes the molecular architecture and canonical functions of CAF-1, integrates emerging evidence across genome maintenance, cell identity, and cancer biology, and evaluates the opportunities and constraints involved in developing CAF-1 as a biomarker and therapeutic vulnerability.