CAF-1 in Replication and Repair: A Critical Genetic Mediator of Synthesis-Coupled Nucleosome Assembly

Eukaryotic genomes are organized into chromatin, a highly compact structure in which DNA is packaged into nucleosomes. Nucleosome formation, where DNA is wrapped around histone proteins, is essential for genome stability. This compaction protects DNA from damage and regulates accessibility of genes. Nucleosomes must be disassembled and reassembled during DNA replication and repair. These processes require precise regulation of histone folding, transfer, and deposition by a diverse network of histone chaperones. Chromatin assembly factor 1 (CAF-1) is a conserved histone chaperone that specifically deposits newly synthesized histones during replication-coupled and repair-coupled nucleosome assembly. The sliding clamp proliferating cell nuclear antigen (PCNA) serves as a regulatory scaffold during these processes by recruiting CAF-1 and many other proteins to sites of DNA replication and repair. Recent structural and biochemical studies have revealed increasingly complex mechanisms underlying PCNA-mediated CAF-1 recruitment, involving multiple protein interaction motifs, DNA-binding domains, and regulatory mechanisms that ensure efficient nucleosome assembly. This review summarizes current advances in understanding the molecular mechanisms by which human and yeast CAF-1 complexes are recruited to sites of DNA synthesis and how CAF-1 function is coordinated with other histone chaperones during replication and repair. These studies have provided important insights into how cells coordinate DNA metabolism with epigenome maintenance to preserve genome integrity.