An hGCN5/TRRAP Histone Acetyltransferase Complex Co-activates BRCA1 Transactivation Function through Histone Modification

Hajime Oishi,Làszlò Tora,Hirochika Kitagawa,Osamu Wada,Shinichiro Takezawa,Laszlo Tora,Madoka Kouzu-Fujita,Ichiro Takada,Tetsu Yano,Junn Yanagisawa,Shigeaki Kato

doi:10.1074/jbc.m510157200

Hajime Oishi, Làszlò Tora + Show 9 more

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https://doi.org/10.1074/jbc.m510157200

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Abstract

It is well established that genetic mutations that impair BRCA1 function predispose women to early onset of breast and ovarian cancer. However, the co-regulatory factors that support normal BRCA1 functions remain to be identified. Using a biochemical approach to search for such co-regulatory factors, we identified hGCN5, TRRAP, and hMSH2/6 as BRCA1-interacting proteins. Genetic mutations in the C-terminal transactivation domain of BRCA1, as found in breast cancer patients (Chapman, M. S., and Verma, I. M. (1996) Nature 382, 678-679), caused the loss of physical interaction between BRCA1 and TRRAP and significantly reduced the co-activation of BRCA1 transactivation function by hGCN5/TRRAP. The reported transcriptional squelching between BRCA1 and estrogen receptor alpha (Fan, S., Wang, J., Yuan, R., Ma, Y., Meng, Q., Erdos, M. R., Pestell, R. G., Yuan, F., Auborn, K. J., Goldberg, I. D., and Rosen, E. M. (1999) Science 284, 1354-1356) was rescued by the overexpression of TRRAP or hGCN5. Histone acetyltransferase hGCN5 activity appeared to be indispensable for coregulator complex function in both BRCA1-mediated gene regulation and DNA repair. Biochemical purification of the hGCN5/TRRAP-containing complex suggested that hGCN5/TRRAP formed a complex with hMSH2/hMSH6, presumably as a novel subclass of hGCN5/TRRAP-containing known TFTC (TBP-free TAF-containing)-type histone acetyltransferase complex (hTFTC, hPCAF, and hSTAGA) (Yanagisawa, J., Kitagawa, H., Yanagida, M., Wada, O., Ogawa, S., Nakagomi, M., Oishi, H., Yamamoto, Y., Nagasawa, H., McMahon, S. B., Cole, M. D., Tora, L., Takahashi, N., and Kato, S. (2002) Mol. Cell 9, 553-562). Unlike other subclasses, the isolated complex harbored a previously unknown combination of components including hMSH2 and hMSH6, major components of the BRCA1 genome surveillance repair complex (BASC). Thus, our results suggested that the multiple BRCA1 functions require a novel hGCN5/TRRAP histone acetyltransferase complex subclass.

Highlights

Germ line mutations in BRCA1 are known to predispose women to the early onset of breast and ovarian cancer [1, 2]
Biochemical Purification of hGCN5 and TRRAP as BRCA1 Interactants—To identify the co-regulators responsible for BRCT function, we biochemically purified protein complexes that interacted with BRCT
As hMSH2 and hMSH6 are thought to be major components of the BRCA1 genome surveillance repair complex (BASC) [29, 30] along with other DNA repair response proteins, it was possible that BASC was trapped to the BRCT domain along with the hGCN5/TRRAP complex

Summary

Introduction

Germ line mutations in BRCA1 are known to predispose women to the early onset of breast and ovarian cancer [1, 2]. ER␣ is a member of the nuclear receptor gene superfamily, acting as a hormone-dependent transcription factor, and is known to require a number of chromatin remodeling and histone modification complexes. A BRCA1 HAT Complex and Histone Acetylation vator complexes have already been reported to support the hormoneinduced transactivation function of hER␣ [19, 21], it is possible that BRCA1 and ER␣ share a common co-regulator complex. To address this issue, we searched for a co-activator complex common to both hER␣ and BRCT and biochemically identified a TRRAP/hGCN complex [23, 24]. Our study suggested that a novel hGCN5/TRRAP HAT complex subclass is required for the multiple functions of BRCA1

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