Our interest: Ubiquitination of proteins is a post-translational modification required for a wide spectrum of biological functions, and defects in several processes involving ubiquitination underlie human diseases. The best characterized ubiquitination reaction involves the formation of polyubiquitin chains, leading to the degradation of target proteins by the proteasome. However, ubiquitination is a complex modification that also mediates cellular functions other than protein degradation. Protein modification by ubiquitin is a reversible reaction and specific proteases can remove the ubiquitin moiety.A vast repertoire of deubiquitinases (DUBs), including approximately 80 genes, are encoded by the human genome, and are emerging as important regulators of the ubiquitination-mediated processes.

As the DUBs are largely unknown, establishing the biological functions and the molecular mechanisms of these proteases is not only a crucial step toward understanding ubiquitin-mediated signaling, but is also a fundamental aspect of cancer biology. We use functional genomics and proteomics approaches to determine the functions and mechanisms of action of DUB enzymes. Our investigations are primarily on DUB genes that are important for the expression and stability of the genome. We are focusing currently on the characterization of BAP1 (BRCA1 Associated Protein 1) deubiquitinase. BAP1 interacts with the breast cancer susceptibility gene BRCA1 and the transcription factor YY1 (Yin Yang 1), two proteins involved in transcription, DNA damage/repair and cell cycle checkpoints.


Publications:

Andrew A. Horwitz, El Bachir Affar, George F. Heine, Yang shi, Jeffrey D. Parvin. A novel mechanism for transcriptional repression dependent on the BRCA1 E3 ubiquitin ligase. Proc. Natl. Acad. Sci. In press, (2007)

Yu May Ma, Emmanuel Boucrot, Judit Villen, El Bachir Affar, Steven P. Gygi, Heinrich G. Gottlinger and Tomas Kirchhausen. Targeting of AMSH to endosomes is required for EGF receptor degradation. Journal of Biological Chemistry, 282(13):9805-9812, (2007)

El Bachir Affar, Margaret Po-shan Luke, Frédérique Gay, Dominica Calvo, Guangchao Sui, Robert S. Weiss, En Li, and Yang Shi. Targeted Ablation of Par-4 Reveals a Cell-Type Specific Susceptibility To Apoptosis-Inducing Agents. Cancer Research, 66(7):3456-3462, (2006)

El Bachir Affar, Frédérique Gay, Yujiang Shi, Huifei Liu, Maite Huarte, Su Wu, Collins Tucker, En Li, and Yang Shi. Essential dosage-dependent functions of the transcription factor Yin Yang 1 in late embryonic development and cell cycle progression. Molecular and Cellular Biology, 26(9):3565-3581, (2006)

Guangchao Sui, El Bachir Affar, Yujiang Shi, Chrystelle Brignone, Nathan R. Wall, Peng Yin, Mary Donohoe, Dominica Calvo, Margaret P. Luke, Steven R. Grossman, Yang Shi. Yin Yang 1 is a negative regulator of p53. Cell, 117(7): 859-872, (2004)

Xu Gang Xia, Hongxia Zhou, Hongliu Ding, El Bachir Affar, Yang Shi and Zuoshang Xu. An enhanced U6 promoter for synthesis of short hairpin RNA.
Nucleic Acids Res., 31(17): e100, (2003)

Hongliu Ding, Dianne S. Schwarz, Alex Keene, El Bachir Affar, Laura Fenton, Xu Gang Xia, Yang Shi, Phillip D. Zamore, Zuoshang Xu. Selective silencing by RNAi of a dominant allele that causes amyotrophic lateral sclerosis. Aging Cell, 2(4): 209-217, (2003)

Yujiang Shi, Jun-ichi Sawada, Guangchao Sui, El Bachir Affar, Johnathan R. Whetstine, Fei Lan, Hidesato Ogawa, Margaret Po-Shan Luke, Yoshihiro Nakatani and Yang Shi. Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature, 422(6933):735-738, (2003)

Guangchao Sui, Christina Soohoo, El Bachir Affar, Frédérique Gay, Yujiang Shi, William Forrester, and Yang Shi. A DNA vector-based RNAi technology to suppress gene expression in mammalian cells. Proc. Natl. Acad. Sci., 99:5515-5520, (2002)

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