A team of UC Berkeley researchers presented the first-ever structural model of a protein factor believed to play a crucial role in the expression of the defining genes in embryonic stem cells.

The team’s research, published Monday in the scientific journal PNAS, focused on creating a three-dimensional map of a complex factor in stem cells known as XPC. According to Elisa Zhang, a campus postdoctoral student and lead author of the study, XPC is important for turning on pluripotency genes, which distinguish stem cells from other types of cells.

“Embryonic stem cells are really interesting because they give rise to all tissues of the adult human body, and that has a lot of potential applications for regenerative medicine and drug testing,” Zhang said. “The functionalities of embryonic stem cells are governed by which genes you turn on and off, which is a process called transcriptional regulation, and our lab has been trying to determine the role of XPC in that process.”

Scientists had previously been aware of the factor’s primary function of DNA repair because a mutation in XPC can lead to skin cancer. But Yick Fong, a former UC Berkeley postdoctoral student on the team, recently discovered that XPC also has another function: controlling gene expression.

“My research basically showed that the yeast version of the XPC complex is not active in transcription, whereas the human version is,” Fong said. “This is the basis for thinking that there are some structural differences between human and yeast XPC factors, because these differences might explain why one is involved in transcription and the other is not.”

According to Zhang, modeling these structural variations would be difficult using most methods because XPC is extremely flexible and alternates between multiple states. In order to create an aggregate visualization of the complex, the team used electron microscopy, including cryo-electron microscopy.

The team discovered that the human and yeast XPC are “remarkably similar overall, including where they contact DNA,” according to Zhang. But a key distinction between XPC from yeast and XPC from mammalian cells was at the sites where XPC interacts with OCT-4 and SOX-2, which are the “master regulators” of transcription in stem cells.

“The main takeaway is that this same complex that performs DNA repair somehow was able to evolve this new function, transcriptional regulation of stem cell genes, that didn’t previously exist in single-celled organisms,” Zhang said. “We found that the structural underpinnings for this new function lie where XPC contacts OCT-4 and SOX-2 in mammals, which reflects the critical difference between XPC in mammals and in yeast.”

Zhang said that XPC’s dual functionality is “very unusual” and that further study of XPC could have broader implications for understanding the interplay between DNA repair and transcription, as well as for stem cell research in general.