Nature of DNA sequences at the attachment regions of genes to the nuclear matrix

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Abstract
Matrix‐attached regions (MARs) have been demonstrated to nest origins of replication and transcriptional enhancers. A set of 13 rules is proposed aimed at facilitating the classification of a DNA sequence as a matrix attachment region. These rules, which were deduced from a study of known MARs from other genes and some others identified in our laboratory, are (1) potential origin of replication are MARs; (2) the major class of MARs seclude clusters of AT‐rich motifs and may harbor topoisomerase II binding and cleavage sites; (3) the AT‐rich class of MARs may comprise the DNA sequence motifs ATTA and ATTTA representing core binding sites of homeotic proteins, implying that MARs may participate in the differential activation of origins of replication and in gene switch during development; (4) the habitat of MARs may include mass binding sites for protein transcription factors; even weak factor binding sites may lead to the formation of tight protein‐DNA supramolecular structures; (5) MARs may contain intrinsically curved DNA; one type is oligo(dA) stretches of 3 to 7 nucleotides spaced every 10.5 nucleotides; (6) a class of MARs may contain kinked DNA, formed by CA, TG, and TA dinucleotides at distances of 5 or 10.5 nucleotides from their centers; the same dinucleotides, known to be abundant in protein recognition sites, may be overrepresented in a special class of MARs; (7) the AT‐rich core of MARs may be flanked, at one or both sides, by sequences that can adopt the left‐handed or triple‐helical DNA structure; these include TG, TA, GC repeats and polypurine or polypyrimidine stretches; (8) palindromic (dyad symmetry) sequences, able to form cruciform structures when the DNA is under torsional strain may be found within MARs, and more so when the MAR is also an origin of replication; (9) transcriptional enhancers may be MARs; (10) a class of MARs may be composed of stretches of GA‐rich DNA alternating with CT‐rich stretches, 5–50 nucleotides long; (11) a class of MARs may be enriched in TG boxes, usually 6–12 nucleotides long, such as TGTTTTGGGG; this type of MAR occurs in the 3′‐untranslated region of several genes, builds up the chromosome telomeres, and is highly recombinogenic; (12) a small fraction of Alu sequences might have MAR activity. This might depend on the number and distance from one another of DNA sequence motifs representing protein binding sites; and (13) MARs may coincide with the DNAse I hypersensitive sites of chromatin. It is proposed here that MAR sequences can provide markers for mapping and sequencing the human, and other, genomes. Furthermore, it is proposed that large scale random cloning of MARs might advance our knowledge on the nature of DNA sequences that are used for the initiation of DNA replication, as transcriptional enhancers and as borders between chromatin domains.