RNF168 and USP10 regulate topoisomerase IIα function via opposing effects on its ubiquitylation

Kiran Kumar Naidu Guturi; Miyuki Bohgaki; Toshiyuki Bohgaki; Tharan Srikumar; Deborah Ng; Ramya Kumareswaran; Samah El Ghamrasni; Justin Jeon; Parasvi Patel; Mohamed Saad Eldin; Rob Bristow; Peter Cheung; Grant S Stewart; Brian Raught; Anne Hakem; Razqallah Hakem

doi:10.1038/ncomms12638

RNF168 and USP10 regulate topoisomerase IIα function via opposing effects on its ubiquitylation

Kiran Kumar Naidu Guturi, Miyuki Bohgaki, Toshiyuki Bohgaki, Tharan Srikumar, Deborah Ng, Ramya Kumareswaran, Samah El Ghamrasni, Justin Jeon, Parasvi Patel, Mohamed Saad Eldin, Rob Bristow, Peter Cheung, Grant S Stewart, Brian Raught, Anne Hakem, Razqallah Hakem

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

22 Citations (Scopus)

Abstract

Topoisomerase IIα (TOP2α) is essential for chromosomal condensation and segregation, as well as genomic integrity. Here we report that RNF168, an E3 ligase mutated in the human RIDDLE syndrome, interacts with TOP2α and mediates its ubiquitylation. RNF168 deficiency impairs decatenation activity of TOP2α and promotes mitotic abnormalities and defective chromosomal segregation. Our data also indicate that RNF168 deficiency, including in human breast cancer cell lines, confers resistance to the anti-cancer drug and TOP2 inhibitor etoposide. We also identify USP10 as a deubiquitylase that negatively regulates TOP2α ubiquitylation and restrains its chromatin association. These findings provide a mechanistic link between the RNF168/USP10 axis and TOP2α ubiquitylation and function, and suggest a role for RNF168 in the response to anti-cancer chemotherapeutics that target TOP2.

Original language	English
Pages (from-to)	12638
Journal	Nature Communications
Volume	7
Early online date	25 Aug 2016
DOIs	https://doi.org/10.1038/ncomms12638
Publication status	E-pub ahead of print - 25 Aug 2016

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Guturi, K. K. N., Bohgaki, M., Bohgaki, T., Srikumar, T., Ng, D., Kumareswaran, R., El Ghamrasni, S., Jeon, J., Patel, P., Eldin, M. S., Bristow, R., Cheung, P., Stewart, G. S., Raught, B., Hakem, A., & Hakem, R. (2016). RNF168 and USP10 regulate topoisomerase IIα function via opposing effects on its ubiquitylation. Nature Communications, 7, 12638. Advance online publication. https://doi.org/10.1038/ncomms12638

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title = "RNF168 and USP10 regulate topoisomerase IIα function via opposing effects on its ubiquitylation",

abstract = "Topoisomerase IIα (TOP2α) is essential for chromosomal condensation and segregation, as well as genomic integrity. Here we report that RNF168, an E3 ligase mutated in the human RIDDLE syndrome, interacts with TOP2α and mediates its ubiquitylation. RNF168 deficiency impairs decatenation activity of TOP2α and promotes mitotic abnormalities and defective chromosomal segregation. Our data also indicate that RNF168 deficiency, including in human breast cancer cell lines, confers resistance to the anti-cancer drug and TOP2 inhibitor etoposide. We also identify USP10 as a deubiquitylase that negatively regulates TOP2α ubiquitylation and restrains its chromatin association. These findings provide a mechanistic link between the RNF168/USP10 axis and TOP2α ubiquitylation and function, and suggest a role for RNF168 in the response to anti-cancer chemotherapeutics that target TOP2.",

author = "Guturi, {Kiran Kumar Naidu} and Miyuki Bohgaki and Toshiyuki Bohgaki and Tharan Srikumar and Deborah Ng and Ramya Kumareswaran and {El Ghamrasni}, Samah and Justin Jeon and Parasvi Patel and Eldin, {Mohamed Saad} and Rob Bristow and Peter Cheung and Stewart, {Grant S} and Brian Raught and Anne Hakem and Razqallah Hakem",

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Guturi, KKN, Bohgaki, M, Bohgaki, T, Srikumar, T, Ng, D, Kumareswaran, R, El Ghamrasni, S, Jeon, J, Patel, P, Eldin, MS, Bristow, R, Cheung, P, Stewart, GS, Raught, B, Hakem, A & Hakem, R 2016, 'RNF168 and USP10 regulate topoisomerase IIα function via opposing effects on its ubiquitylation', Nature Communications, vol. 7, pp. 12638. https://doi.org/10.1038/ncomms12638

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T1 - RNF168 and USP10 regulate topoisomerase IIα function via opposing effects on its ubiquitylation

AU - Guturi, Kiran Kumar Naidu

AU - Bohgaki, Miyuki

AU - Bohgaki, Toshiyuki

AU - Srikumar, Tharan

AU - Ng, Deborah

AU - Kumareswaran, Ramya

AU - El Ghamrasni, Samah

AU - Jeon, Justin

AU - Patel, Parasvi

AU - Eldin, Mohamed Saad

AU - Bristow, Rob

AU - Cheung, Peter

AU - Stewart, Grant S

AU - Raught, Brian

AU - Hakem, Anne

AU - Hakem, Razqallah

PY - 2016/8/25

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N2 - Topoisomerase IIα (TOP2α) is essential for chromosomal condensation and segregation, as well as genomic integrity. Here we report that RNF168, an E3 ligase mutated in the human RIDDLE syndrome, interacts with TOP2α and mediates its ubiquitylation. RNF168 deficiency impairs decatenation activity of TOP2α and promotes mitotic abnormalities and defective chromosomal segregation. Our data also indicate that RNF168 deficiency, including in human breast cancer cell lines, confers resistance to the anti-cancer drug and TOP2 inhibitor etoposide. We also identify USP10 as a deubiquitylase that negatively regulates TOP2α ubiquitylation and restrains its chromatin association. These findings provide a mechanistic link between the RNF168/USP10 axis and TOP2α ubiquitylation and function, and suggest a role for RNF168 in the response to anti-cancer chemotherapeutics that target TOP2.

AB - Topoisomerase IIα (TOP2α) is essential for chromosomal condensation and segregation, as well as genomic integrity. Here we report that RNF168, an E3 ligase mutated in the human RIDDLE syndrome, interacts with TOP2α and mediates its ubiquitylation. RNF168 deficiency impairs decatenation activity of TOP2α and promotes mitotic abnormalities and defective chromosomal segregation. Our data also indicate that RNF168 deficiency, including in human breast cancer cell lines, confers resistance to the anti-cancer drug and TOP2 inhibitor etoposide. We also identify USP10 as a deubiquitylase that negatively regulates TOP2α ubiquitylation and restrains its chromatin association. These findings provide a mechanistic link between the RNF168/USP10 axis and TOP2α ubiquitylation and function, and suggest a role for RNF168 in the response to anti-cancer chemotherapeutics that target TOP2.

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DO - 10.1038/ncomms12638

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SN - 2041-1723

VL - 7

SP - 12638

JO - Nature Communications

JF - Nature Communications

ER -

RNF168 and USP10 regulate topoisomerase IIα function via opposing effects on its ubiquitylation

Abstract

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