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Molecular and Cellular Biology, February 2000, p. 868-877, Vol. 20, No. 3
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Modulated Binding of SATB1, a Matrix Attachment Region Protein, to the AT-Rich Sequence Flanking the Major Breakpoint Region of BCL2

Meera Ramakrishnan,1 Wen-Man Liu,2 Patricia A. DiCroce,1 Aleza Posner,1 Jian Zheng,1 Terumi Kohwi-Shigematsu,2 and Theodore G. Krontiris1,*

Division of Molecular Medicine, Beckman Research Institute of the City of Hope National Medical Center, Duarte, California 91010,1 and Ernest Orlando Lawrence Berkeley National Laboratory, Life Sciences Division, University of California, Berkeley, California 947202

Received 17 May 1999/Returned for modification 6 July 1999/Accepted 22 October 1999

The t(14,18) chromosomal translocation that occurs in human follicular lymphoma constitutively activates the BCL2 gene and disrupts control of apoptosis. Interestingly, 70% of the t(14,18) translocations are confined to three 15-bp clusters positioned within a 150-bp region (major breakpoint region or [MBR]) in the untranslated portion of terminal exon 3. We analyzed DNA-protein interactions in the MBR, as these may play some role in targeting the translocation to this region. An 87-bp segment (87MBR) immediately 3' to breakpoint cluster 3 was essential for DNA-protein interaction monitored with mobility shift assays. We further delineated a core binding region within 87MBR: a 33-bp, very AT-rich sequence highly conserved between the human and mouse BCL2 gene (37MBR). We have purified and identified one of the core factors as the matrix attachment region (MAR) binding protein, SATB1, which is known to bind to AT-rich sequences with a high propensity to unwind. Additional factors in nuclear extracts, which we have not yet characterized further, increased SATB1 affinity for the 37MBR target four- to fivefold. Specific binding activity within 37MBR displayed cell cycle regulation in Jurkat T cells, while levels of SATB1 remained constant throughout the cell cycle. Finally, we demonstrated in vivo binding of SATB1 to the MBR, strongly suggesting the BCL2 major breakpoint region is a MAR. We discuss the potential consequences of our observations for both MBR fragility and regulatory function.

* Corresponding author. Mailing address: Division of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Rd., Duarte, CA 91010-3000. Phone: (626) 359-8111, ext. 4297. Fax: (626) 301-8862. E-mail: tkrontir{at}coh.org.

Molecular and Cellular Biology, February 2000, p. 868-877, Vol. 20, No. 3
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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