The Lys63-specific deubiquitinating enzyme BRCC36 is regulated by two scaffold proteins localizing in different subcellular compartments.
BRCC36 is a member of the JAMM/MPN(+) family of zinc metalloproteases that specifically cleaves Lys 63-linked polyubiquitin chains in vitro. We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1. This complex participates in the regulation of BRCA1 localization in response to DNA damage. Here we provide evidence indicating that BRCC36 regulates the abundance of Lys(63)-linked ubiquitin chains at chromatin and that one of its substrates is diubiquitinated histone H2A. Moreover, besides interacting with CCDC98 within the BRCA1-A complex, BRCC36 also associates with another protein KIAA0157, which shares significant sequence homology with CCDC98. Interestingly, although CCDC98 functions as an adaptor of BRCC36 and regulates BRCC36 activity in the nucleus, KIAA0157 mainly localizes in cytosol and activates BRCC36 in the cytoplasm. Moreover, these two complexes appear to exist in fine balance in vivo because reduction of KIAA0157 expression led to an increase of the BRCA1-A complex in the nucleus. Together, these results suggest that scaffold proteins not only participate in the regulation of BRCC36 activity but also determine its subcellular localization and cellular functions.
Feng
Lin
L
Department of Experimental Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Wang
Jiadong
J
Chen
Junjie
J
D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000201:enzymology* / Q000235:genetics; D003600:Cytosol / Q000201:enzymology*; D000072017:Deubiquitinating Enzymes; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism
C520310:ABRAXAS1 protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; D009097:Multienzyme Complexes; D025801:Ubiquitin; D010450:Endopeptidases; C518017:BRCC3 protein, human; D000072017:Deubiquitinating Enzymes