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Molecular and Cellular Biology, August 2009, p. 4519-4526, Vol. 29, No. 16
0270-7306/09/$08.00+0     doi:10.1128/MCB.00195-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

MLL Associates with Telomeres and Regulates Telomeric Repeat-Containing RNA Transcription{triangledown} ,{dagger}

Corrado Caslini,1* James A. Connelly,2 Amparo Serna,3 Dominique Broccoli,4 and Jay L. Hess1

Departments of Pathology,1 Hematology-Oncology,2 Internal Medicine, University of Michigan Medical School, 1301 Catherine, Ann Arbor, Michigan 48109,3 Department of Laboratory Oncology Research, Curtis and Elizabeth Anderson Cancer Institute, Memorial University Medical Center, 4700 Waters Avenue, Savannah, Georgia 314044

Received 11 February 2009/ Returned for modification 19 March 2009/ Accepted 4 June 2009

Mammalian telomeres consist of TTAGGG repeats organized in nucleosomes and associated with a six-protein complex known as shelterin, which preserves telomere structure and protects chromosome ends from the cellular DNA damage response. Recent studies have found that telomeres are transcribed into telomeric UUAGGG repeat-containing RNA (TERRA) starting from subtelomeric regions. TERRA binding at telomeres appears to be involved in cis-based mechanisms of telomeric chromatin organization and maintenance. A number of histone methyltransferases (HMTs) are known to influence telomeric chromatin status; however, the regulatory mechanisms of telomere transcription are poorly understood. Here, we show that the histone 3/lysine 4 (H3/K4) HMT and the transcriptional regulator MLL associate with telomeres and contribute to their H3/K4 methylation and transcription in a telomere length-dependent manner. In human diploid fibroblasts, RNA interference-mediated MLL depletion affects telomere chromatin modification and transcription and induces the telomere damage response. Telomere uncapping through either TRF2 shelterin protein knockdown or exposure to telomere G-strand DNA oligonucleotides significantly increases the transcription of TERRA, an effect mediated by the functional cooperation between MLL and the tumor suppressor p53. In total, our findings identify a previously unrecognized role of MLL in modifying telomeric chromatin and provide evidence for the functional interaction between MLL, p53, and the shelterin complex in the regulation of telomeric transcription and stability.

* Corresponding author. Mailing address: Department of Pathology, University of Michigan Medical School, 5214B Medical Science I, 1301 Catherine Avenue, Ann Arbor MI 48109-0602. Phone: (734) 764-3496. Fax: (734) 936-1951. E-mail: ccaslini{at}med.umich.edu

{triangledown} Published ahead of print on 15 June 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2009, p. 4519-4526, Vol. 29, No. 16
0270-7306/09/$08.00+0     doi:10.1128/MCB.00195-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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