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Genes 2016, 7(9), 69; doi:10.3390/genes7090069

Regulation of BLM Nucleolar Localization

1
Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
2
Divisions of Hematology and Medical Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Richard T. Pomerantz
Received: 15 June 2016 / Revised: 31 August 2016 / Accepted: 14 September 2016 / Published: 21 September 2016
(This article belongs to the Special Issue Replication and Transcription Associated DNA Repair)
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Abstract

Defects in coordinated ribosomal RNA (rRNA) transcription in the nucleolus cause cellular and organismal growth deficiencies. Bloom’s syndrome, an autosomal recessive human disorder caused by mutated recQ-like helicase BLM, presents with growth defects suggestive of underlying defects in rRNA transcription. Our previous studies showed that BLM facilitates rRNA transcription and interacts with RNA polymerase I and topoisomerase I (TOP1) in the nucleolus. The mechanisms regulating localization of BLM to the nucleolus are unknown. In this study, we identify the TOP1-interaction region of BLM by co-immunoprecipitation of in vitro transcribed and translated BLM segments and show that this region includes the highly conserved nuclear localization sequence (NLS) of BLM. Biochemical and nucleolar co-localization studies using site-specific mutants show that two serines within the NLS (S1342 and S1345) are critical for nucleolar localization of BLM but do not affect the functional interaction of BLM with TOP1. Mutagenesis of both serines to aspartic acid (phospho-mimetic), but not alanine (phospho-dead), results in approximately 80% reduction in nucleolar localization of BLM while retaining the biochemical functions and nuclear localization of BLM. Our studies suggest a role for this region in regulating nucleolar localization of BLM via modification of the two serines within the NLS. View Full-Text
Keywords: Bloom’s syndrome; rRNA transcription; BLM; topoisomerase I; growth defects; nucleolar localization Bloom’s syndrome; rRNA transcription; BLM; topoisomerase I; growth defects; nucleolar localization
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MDPI and ACS Style

Tangeman, L.; McIlhatton, M.A.; Grierson, P.; Groden, J.; Acharya, S. Regulation of BLM Nucleolar Localization. Genes 2016, 7, 69.

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