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2016 ; 7
(9
): ä Nephropedia Template TP
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Regulation of BLM Nucleolar Localization
#MMPMID27657136
Tangeman L
; McIlhatton MA
; Grierson P
; Groden J
; Acharya S
Genes (Basel)
2016[Sep]; 7
(9
): ä PMID27657136
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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.
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