Abstract
Germline mutations that inactivate BRCA2 promote early-onset cancer with chromosome instability. Here, we report that BRCA2 regulates the spindle assembly checkpoint (SAC). Previously, we reported that BubR1 acetylation is essential for SAC activity. In this study we show that BRCA2 recruits the PCAF acetyltransferase and aids in BubR1 acetylation during mitosis. In the absence of BRCA2, BubR1 acetylation is abolished, and the level of BubR1 decreases during mitosis. Similarly, Brca2-deficient mouse embryonic fibroblasts exhibited weak SAC activity. Transgenic mice that were engineered to have interruptions in the BRCA2-BubR1 association exhibited marked decrease of BubR1 acetylation, weakened SAC activity, and aneuploidy. These transgenic mice developed spontaneous tumors at 40% penetrance. Moreover, immunohistochemical analyses of human breast cancer specimens suggested that BRCA2 mutation and BubR1 status is closely linked. Our results provide an explanation for how mutation of BRCA2 can lead to chromosome instability without apparent mutations in SAC components. BRCA2-deficient cells exhibit aneuploidy. Choi etal. show that BRCA2 regulates the spindle assembly checkpoint (SAC), recruiting PCNA for prometaphase-specific BubR1 acetylation. Disruption of BRCA2-BubR1 association diminishes BubR1 acetylation in mitosis, disrupts the SAC, and is associated with the development of spontaneous cancers in mice.
| Original language | English |
|---|---|
| Pages (from-to) | 295-308 |
| Number of pages | 14 |
| Journal | Developmental Cell |
| Volume | 22 |
| Issue number | 2 |
| DOIs | |
| State | Published - 14 Feb 2012 |
Bibliographical note
Funding Information:Brca2 f11 mice were a gift from A. Berns (NCI, The Netherlands), and the I-SceI expression plasmid (pCBASce) and I-SceI reporter plasmids were from A.J. Pierce (University of Kentucky). We are grateful to Drs. M. Petronczki (Claire Hall Laboratories, London) and M. Kwon (Dana Farber Cancer Institute, Boston) for critical reading of the manuscript, and Dr. H-W. Lee (Yonsei University, Seoul, Korea) for help with generating mB2-9 transgenic mouse. This work was supported by the Basic Science Research Program (2008-0059996) and Grants from NRF of Korea (2009-0093927 and 2010-0026104). Flow cytometric analyses were supported by the RCFC (2005-0048590). E.C. was supported by the Priority Research Centers Program (2010-0029696).
