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Dysfunction of chromosomal loop attachment sites: illegitimate recombination linked to matrix association regions and
A O Sperry1, V C Blasquez, W T Garrard
1Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas 75235.
Abstract:
A family of A + T-rich sequences termed MARs ("matrix association regions") mediate chromosomal loop attachment. Here we demonstrate that several MARs both specifically bind and contain multiple sites of cleavage by topoisomerase II, a major protein of the mitotic chromosomal scaffold. Interestingly, "hotspots" of enzyme cutting occur within the MAR of the mouse immunoglobulin kappa-chain gene at the breakpoint of a previously described chromosomal translocation. Since topoisomerase II can mediate illegitimate recombination in prokaryotes, we explored further the possibility that MARs might be targets for this process in eukaryotes. We found that a MAR had been deleted from one of the two rabbit immunoglobulin kappa-chain genes and that MARs reside next to a long interspersed repetitive element within the recombination junction of a human ring chromosome 21. These results, taken together with other accounts of nonhomologous recombination, lead to the proposal that a dysfunction of MARs is illegitimate recombination.
Insights
Matrix association regions (MARs) bind and are cleaved by topoisomerase II. MAR dysfunction may cause illegitimate recombination, a type of DNA rearrangement observed in gene studies and chromosomal abnormalities.
Area of Science:
- Genetics
- Molecular Biology
- Chromosomal Structure
Background:
- Matrix association regions (MARs) are A + T-rich sequences involved in chromosomal loop attachment.
- Topoisomerase II is a key protein in the mitotic chromosomal scaffold.
Purpose of the Study:
- To investigate the interaction between MARs and topoisomerase II.
- To explore the role of MARs in illegitimate recombination.
Main Methods:
- Binding assays to assess MARs' interaction with topoisomerase II.
- Analysis of MARs in specific gene loci and chromosomal abnormalities.
- Comparison with known mechanisms of illegitimate recombination.
Main Results:
- MARs specifically bind and are cleaved by topoisomerase II.
- Topoisomerase II cutting hotspots are found in MARs at translocation breakpoints.
- MAR deletion and association with repetitive elements at recombination junctions were observed.
Conclusions:
- MARs are direct targets of topoisomerase II.
- MAR dysfunction is proposed as a mechanism for illegitimate recombination in eukaryotes.