Origins of replication and the nuclear matrix: the DHFR domain as a paradigm

The eukaryotic genome appears to be organized in a loopwise fashion by periodic attachment to the nuclear matrix. The proposal that a chromatin loop corresponds to a functional domain has stirred interest in the properties of the DNA sequences at the bases of these loops, the matrix-attached regions (MARs). Evidence has been presented suggesting that certain MARs act as boundary elements isolating domains from their chromosomal context. MARs have also been found in the vicinity of promoters and enhancers and they could act by displacing these cis-regulatory elements into the proper nuclear subcompartment. Attachment to the matrix might also play a role in DNA replication. A large body of evidence indicates that replication occurs on the nuclear matrix. This implies that any DNA sequence will be attached to the matrix at a certain time during the cell cycle. This transient mode of attachment contrasts with the proposed permanent attachment of origins of DNA replication with the nuclear matrix. While some data exist that support this suggestion, the current lack of understanding of the mammalian replication origin precludes definitive conclusions regarding the role of MARs in the initiation process.