Researchers are interested in ways that cells can efficiently turn genes on or off, and one of the newest mechanisms is dubbed "NEDDylation," which Yeh helped to find 10 years ago. This process requires multiple enzymes to attach NEDD8 to other proteins.
To find proteins that can be altered by NEDD8, the four-member research team used yeast as their experimental platform, and SENP8 as a tool. This enzyme is known to be able to separate NEDD8 from the proteins it binds to. In this way, they could use SNEP8 "as bait" to fish for protein complexes held together by NEDD8.
They first found that BCA3 binds to SENP8 and was modified byNEDD8, and then discovered that this complex affects NFkB signaling. It does this by binding on to p65, one of the two proteins that make up NFkB proteins, the researchers say. "NEDD8 modified BCA3 regulates the activity of NFkB, but BCA3 alone does not have any impact on NFkB," says Yeh.
Then they looked at how this NEDDylation further works to suppress the ability of NFkB to transcribe (activate) other genes. Here the investigators found SITR1, the molecule known to prolong life span in several other species. SITR1 is a histone deacetylase, a protein that blocks transcription factors from regulating genes. "When NEDD8 modified BCA3, it binds to p65 and recruits SITR1 to suppress NFkB-mediated transcription," Yeh said.
Finally, the researchers discovered that estrogen blocks NEDD8 from modifying BCA3, a finding which goes some way to "explaining estrogen's pro-life effect in breast cancer cells," Yeh says. "Estrogen could enhance the sur