By Michele Sequeira

Learning From a Rare Disease

In hopes of improving cancer treatments, Hua-Ying Fan studies people with Cockayne syndrome, who don’t get cancer

Hua-Ying Fan, PhD, studies the cells of people who don't get cancer. These people have an inherited disorder called Cockayne syndrome and, unfortunately, they don't live long enough to develop cancer. But by studying their cells, Fan may be able to help them and help people with cancer, too.

Fan is a molecular medicine scientist at The University of New Mexico Comprehensive Cancer Center. In studying the differences between the cells of those with Cockayne syndrome and those who don't have it, Fan and her research team discovered the importance of a protein called CSB.

The cells of people with Cockayne syndrome don't make CSB. They also have high levels of molecules called reactive oxygen species. Normal cellular functions produce reactive oxygen species, but when too much builds up, these molecules damage the cell's DNA, which stresses the cell and hastens its death.

"[Cockayne] is a premature aging syndrome," says Fan. "The cell just dies."

Fan's team discovered that in healthy cells, the CSB protein helps to repair DNA damage caused by reactive oxygen species. And they discovered that CSB must work with another protein called PARP1.

PARP1, Fan says, goes to where the DNA is damaged and then attracts CSB to that spot. The CSB and PARP1 work together to repair the DNA. Neither protein can efficiently repair DNA on its own.

Fan's team discovered a further link between the two proteins.

"When cells are stressed," she says, "a different set of genes has to be turned on, in addition to [those for] housekeeping functions. Those gene products have to be generated."

Those gene products are proteins that lower reactive oxygen species levels when they become too high. Again, PARP1 and CSB combine to transcribe DNA and create proteins that fight reactive oxygen species.

So in healthy cells, CSB helps not only to fight excess reactive oxygen species but also to repair the damage they create. The cells of people with Cockayne syndrome lack CSB and can neither lower reactive oxygen species levels nor repair their DNA damage.

Fan hopes to use this research to develop ways to make existing cancer drugs more potent. Cancer drugs that work by interfering with PARP1 could make a good choice. If resistance to these drugs develops, Fan thinks that preventing CSB and PARP1 from working together could induce cancer cells to die faster.

"There's more motivation to look for inhibitors for CSB," she says.

Fan is looking forward to discovering potential drugs that inhibit CSB for people with cancer - or that take its place, for people with Cockayne syndrome.

The paper, "Poly(ADP-ribose) polymerase 1 (PARP1) promotes oxidative stress-induced association of Cockayne syndrome group B protein with chromatin," was published in the Journal of Biochemistry and Molecular Biology on September 28, 2018. Authors are: Erica L. Boetefuer, Robert J. Lake, Kostiantyn Dreval, and Hua-Ying Fan.

Categories: Comprehensive Cancer Center