Guan et al. suggest a function for mysterious DNA segments that are scattered throughout the mammalian genome. The segments curtail most or all replication within their boundaries and might allow cells to fine-tune the pace of DNA duplication.

Different parts of the genome replicate at different times in S phase. Some sections start the process early, whereas others procrastinate. A third category contains the temporal transition regions, or TTRs, that start replicating at the beginning of S phase but don't finish until late. How cells control the timing of TTR duplication is unknown. A possible clue comes from the gene locus for the antibody heavy chain. In embryonic stem cells, these genes are located within a TTR. But early in B cell development, the TTR appears to vanish, and the entire locus replicates early. This indicates that the TTR harbors latent replication origins that can be turned on. Guan et al. wanted to discover how.

Genes that are being transcribed typically duplicate before inactive ones. To test whether transcription affects TTR replication, Guan et al. inserted gene-containing DNA segments into the heavy chain TTR of stem cells and switched them on. Although the insertions were expressed, sometimes at a high level, they didn't change the TTR's replication schedule. Increasing histone acetylation, a marker of working genes, also had no effect. Even when the researchers slipped replication origins from another locus into the TTR, DNA duplication rarely began.

In effect, the heavy chain TTR is a replication dead zone where origins remain quiet except during specific developmental events. The repression mechanism remains unclear, but the researchers suggest that a TTR's status could depend on higher-order chromatin structure or its position in the nucleus. TTRs could serve as speed bumps during DNA copying, preventing the early starting sections from overshooting and causing premature duplication of the laggards.


et al
J. Cell Biol.