Oncotarget

Research Papers:

Aurora kinase B dependent phosphorylation of 53BP1 is required for resolving merotelic kinetochore-microtubule attachment errors during mitosis

Haibo Wang, Bin Peng, Raj K. Pandita, David A. Engler, Risë K. Matsunami, Pavana M. Hegde, Brian E. Butler, Tej K. Pandita, Sankar Mitra, Bo Xu and Muralidhar L. Hegde _

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Oncotarget. 2017; 8:48671-48687. https://doi.org/10.18632/oncotarget.16225

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Abstract

Haibo Wang1,2, Bin Peng3, Raj K. Pandita1, David A. Engler4, Risë K. Matsunami4, Xingzhi Xu3, Pavana M. Hegde1, Brian E. Butler1, Tej K. Pandita1,5, Sankar Mitra1,5, Bo Xu6 and Muralidhar L. Hegde1,2,5

1 Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX, USA

2 Houston Methodist Neurological Institute, Houston, TX, USA

3 Beijing Key Laboratory of DNA Damage Response and College of Life Science, Capital Normal University, Beijing, China

4 Proteomics Programmatic Core Laboratory, Houston Methodist Research Institute, Houston, TX, USA

5 Weill Medical College of Cornell University, New York, NY, USA

6 Department of Oncology, Southern Research Institute, Birmingham, AL, USA

Correspondence to:

Muralidhar L. Hegde, email:

Haibo Wang, email:

Keywords: 53BP1, aneuploidy, chromosome segregation, merotelic attachment

Received: March 02, 2017 Accepted: March 03, 2017 Published: March 15, 2017

Abstract

Defects in resolving kinetochore-microtubule attachment mistakes during mitosis is linked to chromosome instability associated with carcinogenesis as well as resistance to cancer therapy. Here we report for the first time that tumor suppressor p53-binding protein 1 (53BP1) is phosphorylated at serine 1342 (S1342) by Aurora kinase B both in vitro and in human cells, which is required for optimal recruitment of 53BP1 at kinetochores. Furthermore, 53BP1 staining normally localized on the outer kinetochore, extended to the whole kinetochore when it is merotelically-attached, in concert with mitotic centromere-associated kinesin. Kinetochore-binding of pS1342-53BP1 is essential for efficient resolving of merotelic attachment, a spontaneous kinetochore-microtubule connection error that usually causes aneuploidy. Consistently, loss of 53BP1 results in significant increase in lagging chromosome events, micronuclei formation and aneuploidy, due to the unresolved merotely in both cancer and primary cells, which is prevented by ectopic wild type 53BP1 but not by the nonphophorylable S1342A mutant. We thus document a novel DNA damage-independent function of 53BP1 in maintaining faithful chromosome segregation during mitosis.


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