Much as an automobile assembly line slows if engines are in short supply, DNA replication slackens if the cell is low on new histones, Mejlvang et al. reveal.
To replicate their DNA, cells require ample amounts of nucleotides. But whether the availability of fresh histones, which package DNA into nucleosomes, also controls the rate of DNA copying is unclear. Yeast can complete S phase without new histones, researchers have found. However, studies that blocked protein synthesis in mammalian cells showed that DNA duplication falters, suggesting that a scarcity of histones can impede replication.
Mejlvang et al. addressed the issue in mammalian cells by blocking two regulatory factors that are essential for synthesizing all six of the canonical histones. The resulting histone shortage slowed the advance of replication forks but didn’t prevent the firing of new replication origins. Cells disassemble chromatin during DNA copying, and the first step in restoring it is the formation of nucleosomes behind the replication fork. Mejlvang et al. found that nucleosomes didn’t reform properly when histones were in short supply. The researchers also showed that blocking nucleosome construction delays replication fork progression and prevents the departure of PCNA, an enzyme that coordinates multiple functions at replication forks, including DNA synthesis and nucleosome assembly.
Nucleotide shortages trigger DNA damage checkpoints. But to the researchers’ surprise, histone scarcity didn’t initially trip these checkpoints, indicating that cells can wait for supplies of histones to build up without jeopardizing genome integrity. The next challenge is resolving how cells sense that nuclesome assembly is incomplete.
Text by Mitch Leslie