HERC2 inactivation abrogates nucleolar localization of RecQ helicases BLM and WRN

Abstract The nucleolus is a nuclear structure composed of ribosomal DNA (rDNA), and functions as a site for rRNA synthesis and processing. The rDNA is guanine-rich and prone to form G-quadruplex (G4), a secondary structure of DNA. We have recently found that HERC2, an HECT ubiquitin ligase, promotes...

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Autores principales:	Mingzhang Zhu, Wenwen Wu, Yukiko Togashi, Weixin Liang, Yasuo Miyoshi, Tomohiko Ohta
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8dc79e6081f24ef6a68a4ba40ee58c67
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spelling	oai:doaj.org-article:8dc79e6081f24ef6a68a4ba40ee58c672021-12-02T14:01:21ZHERC2 inactivation abrogates nucleolar localization of RecQ helicases BLM and WRN10.1038/s41598-020-79715-y2045-2322https://doaj.org/article/8dc79e6081f24ef6a68a4ba40ee58c672021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-79715-yhttps://doaj.org/toc/2045-2322Abstract The nucleolus is a nuclear structure composed of ribosomal DNA (rDNA), and functions as a site for rRNA synthesis and processing. The rDNA is guanine-rich and prone to form G-quadruplex (G4), a secondary structure of DNA. We have recently found that HERC2, an HECT ubiquitin ligase, promotes BLM and WRN RecQ DNA helicases to resolve the G4 structure. Here, we report the role of HERC2 in the regulation of nucleolar localization of the helicases. Furthermore, HERC2 inactivation enhances the effects of CX-5461, an inhibitor of RNA polymerase I (Pol I)-mediated transcription of rRNA with an intrinsic G4-stabilizing activity. HERC2 depletion or homozygous deletion of the C-terminal HECT domain of HERC2 prevented the nucleolar localization of BLM and WRN, and inhibited relocalization of BLM to replication stress-induced nuclear RPA foci. HERC2 colocalized with fibrillarin and Pol I subunit RPA194, both of which are required for rRNA transcription. The HERC2 dysfunction enhanced the suppression of pre-rRNA transcription by CX-5461. These results suggest the effect of HERC2 status on the functions of BLM and WRN on rRNA transcription in the nucleolus. Since HERC2 is downregulated in numerous cancers, this effect may be clinically relevant considering the beneficial effects of CX-5461 in cancer treatments.Mingzhang ZhuWenwen WuYukiko TogashiWeixin LiangYasuo MiyoshiTomohiko OhtaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mingzhang Zhu Wenwen Wu Yukiko Togashi Weixin Liang Yasuo Miyoshi Tomohiko Ohta HERC2 inactivation abrogates nucleolar localization of RecQ helicases BLM and WRN
description	Abstract The nucleolus is a nuclear structure composed of ribosomal DNA (rDNA), and functions as a site for rRNA synthesis and processing. The rDNA is guanine-rich and prone to form G-quadruplex (G4), a secondary structure of DNA. We have recently found that HERC2, an HECT ubiquitin ligase, promotes BLM and WRN RecQ DNA helicases to resolve the G4 structure. Here, we report the role of HERC2 in the regulation of nucleolar localization of the helicases. Furthermore, HERC2 inactivation enhances the effects of CX-5461, an inhibitor of RNA polymerase I (Pol I)-mediated transcription of rRNA with an intrinsic G4-stabilizing activity. HERC2 depletion or homozygous deletion of the C-terminal HECT domain of HERC2 prevented the nucleolar localization of BLM and WRN, and inhibited relocalization of BLM to replication stress-induced nuclear RPA foci. HERC2 colocalized with fibrillarin and Pol I subunit RPA194, both of which are required for rRNA transcription. The HERC2 dysfunction enhanced the suppression of pre-rRNA transcription by CX-5461. These results suggest the effect of HERC2 status on the functions of BLM and WRN on rRNA transcription in the nucleolus. Since HERC2 is downregulated in numerous cancers, this effect may be clinically relevant considering the beneficial effects of CX-5461 in cancer treatments.
format	article
author	Mingzhang Zhu Wenwen Wu Yukiko Togashi Weixin Liang Yasuo Miyoshi Tomohiko Ohta
author_facet	Mingzhang Zhu Wenwen Wu Yukiko Togashi Weixin Liang Yasuo Miyoshi Tomohiko Ohta
author_sort	Mingzhang Zhu
title	HERC2 inactivation abrogates nucleolar localization of RecQ helicases BLM and WRN
title_short	HERC2 inactivation abrogates nucleolar localization of RecQ helicases BLM and WRN
title_full	HERC2 inactivation abrogates nucleolar localization of RecQ helicases BLM and WRN
title_fullStr	HERC2 inactivation abrogates nucleolar localization of RecQ helicases BLM and WRN
title_full_unstemmed	HERC2 inactivation abrogates nucleolar localization of RecQ helicases BLM and WRN
title_sort	herc2 inactivation abrogates nucleolar localization of recq helicases blm and wrn
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/8dc79e6081f24ef6a68a4ba40ee58c67
work_keys_str_mv	AT mingzhangzhu herc2inactivationabrogatesnucleolarlocalizationofrecqhelicasesblmandwrn AT wenwenwu herc2inactivationabrogatesnucleolarlocalizationofrecqhelicasesblmandwrn AT yukikotogashi herc2inactivationabrogatesnucleolarlocalizationofrecqhelicasesblmandwrn AT weixinliang herc2inactivationabrogatesnucleolarlocalizationofrecqhelicasesblmandwrn AT yasuomiyoshi herc2inactivationabrogatesnucleolarlocalizationofrecqhelicasesblmandwrn AT tomohikoohta herc2inactivationabrogatesnucleolarlocalizationofrecqhelicasesblmandwrn
_version_	1718392212018954240

HERC2 inactivation abrogates nucleolar localization of RecQ helicases BLM and WRN

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