MRE11 and UBR5 Co-Operate to Suppress RNF168-Mediated Fusion of Dysfunctional Telomeres

TRF2 is part of the shelterin complex that hides telomeric DNA ends and prevents the activation of the cNHEJ pathway that can lead to chromosomal fusion. TRF2, however, also actively suppresses the cNHEJ pathway by recruiting two proteins, MRE11 and UBR5. MRE11 binds BRCC3, which in turn deubiquitin...

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Autores principales:	Yongjian Tang, Joydeep Mukherjee, Russell O. Pieper
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	telomere MRE11 UBR5 fusion glioma Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/fcdc36a04f7d47fc82b053dc8ab98103
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spelling	oai:doaj.org-article:fcdc36a04f7d47fc82b053dc8ab981032021-11-22T04:28:43ZMRE11 and UBR5 Co-Operate to Suppress RNF168-Mediated Fusion of Dysfunctional Telomeres2234-943X10.3389/fonc.2021.772233https://doaj.org/article/fcdc36a04f7d47fc82b053dc8ab981032021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.772233/fullhttps://doaj.org/toc/2234-943XTRF2 is part of the shelterin complex that hides telomeric DNA ends and prevents the activation of the cNHEJ pathway that can lead to chromosomal fusion. TRF2, however, also actively suppresses the cNHEJ pathway by recruiting two proteins, MRE11 and UBR5. MRE11 binds BRCC3, which in turn deubiquitinates γH2AX deposited at exposed telomeric DNA ends and limits RNF168 recruitment to the telomere. UBR5, in contrast directly ubiquitinates and destroys RNF168. The loss of telomeric RNF168 in turn blocks the subsequent recruitment of 53BP1 and prevents the cNHEJ-mediated fusion of chromosomes with exposed telomeric DNA ends. Although MRE11 and UBR5 are both involved in the control of telomeric RNF168 levels and the chromosome fusion process, their relative contributions have not been directly addressed. To do so we genetically suppressed MRE11 and UBR5 alone or in combination in glioma cell lines which we previously showed contained dysfunctional telomeres that were dependent on TRF2 for suppression of telomeric fusion and monitored the effects on events associated with telomere fusion. We here show that while suppression of either MRE11 or UBR5 alone had minimal effects on RNF168 telomeric accumulation, 53BP1 recruitment, and telomeric fusion, their combined suppression led to significant increases in RNF168 and 53BP1 telomeric recruitment and telomeric fusion and eventually cell death, all of which were reversible by suppression of RNF168 itself. These results show that MRE11 and UBR5 co-operate to suppress fusion at dysfunctional telomeres.Yongjian TangYongjian TangJoydeep MukherjeeRussell O. PieperFrontiers Media S.A.articletelomereMRE11UBR5fusiongliomaNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	telomere MRE11 UBR5 fusion glioma Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	telomere MRE11 UBR5 fusion glioma Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Yongjian Tang Yongjian Tang Joydeep Mukherjee Russell O. Pieper MRE11 and UBR5 Co-Operate to Suppress RNF168-Mediated Fusion of Dysfunctional Telomeres
description	TRF2 is part of the shelterin complex that hides telomeric DNA ends and prevents the activation of the cNHEJ pathway that can lead to chromosomal fusion. TRF2, however, also actively suppresses the cNHEJ pathway by recruiting two proteins, MRE11 and UBR5. MRE11 binds BRCC3, which in turn deubiquitinates γH2AX deposited at exposed telomeric DNA ends and limits RNF168 recruitment to the telomere. UBR5, in contrast directly ubiquitinates and destroys RNF168. The loss of telomeric RNF168 in turn blocks the subsequent recruitment of 53BP1 and prevents the cNHEJ-mediated fusion of chromosomes with exposed telomeric DNA ends. Although MRE11 and UBR5 are both involved in the control of telomeric RNF168 levels and the chromosome fusion process, their relative contributions have not been directly addressed. To do so we genetically suppressed MRE11 and UBR5 alone or in combination in glioma cell lines which we previously showed contained dysfunctional telomeres that were dependent on TRF2 for suppression of telomeric fusion and monitored the effects on events associated with telomere fusion. We here show that while suppression of either MRE11 or UBR5 alone had minimal effects on RNF168 telomeric accumulation, 53BP1 recruitment, and telomeric fusion, their combined suppression led to significant increases in RNF168 and 53BP1 telomeric recruitment and telomeric fusion and eventually cell death, all of which were reversible by suppression of RNF168 itself. These results show that MRE11 and UBR5 co-operate to suppress fusion at dysfunctional telomeres.
format	article
author	Yongjian Tang Yongjian Tang Joydeep Mukherjee Russell O. Pieper
author_facet	Yongjian Tang Yongjian Tang Joydeep Mukherjee Russell O. Pieper
author_sort	Yongjian Tang
title	MRE11 and UBR5 Co-Operate to Suppress RNF168-Mediated Fusion of Dysfunctional Telomeres
title_short	MRE11 and UBR5 Co-Operate to Suppress RNF168-Mediated Fusion of Dysfunctional Telomeres
title_full	MRE11 and UBR5 Co-Operate to Suppress RNF168-Mediated Fusion of Dysfunctional Telomeres
title_fullStr	MRE11 and UBR5 Co-Operate to Suppress RNF168-Mediated Fusion of Dysfunctional Telomeres
title_full_unstemmed	MRE11 and UBR5 Co-Operate to Suppress RNF168-Mediated Fusion of Dysfunctional Telomeres
title_sort	mre11 and ubr5 co-operate to suppress rnf168-mediated fusion of dysfunctional telomeres
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/fcdc36a04f7d47fc82b053dc8ab98103
work_keys_str_mv	AT yongjiantang mre11andubr5cooperatetosuppressrnf168mediatedfusionofdysfunctionaltelomeres AT yongjiantang mre11andubr5cooperatetosuppressrnf168mediatedfusionofdysfunctionaltelomeres AT joydeepmukherjee mre11andubr5cooperatetosuppressrnf168mediatedfusionofdysfunctionaltelomeres AT russellopieper mre11andubr5cooperatetosuppressrnf168mediatedfusionofdysfunctionaltelomeres
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MRE11 and UBR5 Co-Operate to Suppress RNF168-Mediated Fusion of Dysfunctional Telomeres

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