Microscopic mimicry

Yale researchers have solved a cancer mystery on a molecular scale, and their solution could help advance the treatment of several cancers.

The mystery revolved around the well-known BRCA2 gene and a tiny protein named DSS1. Ordinarily, the BRCA2 gene acts to suppress tumors, because the BRCA2 protein it produces helps to repair DNA breaks. But certain mutated variants of the gene—variants closely associated with breast, ovarian, and other cancers—fail to perform correctly. As a result, genes with flaws proliferate, and some of them may lead to cancer.

Researchers knew that the BRCA2 protein depends on DSS1 to function, and that faulty DSS1 leads to hypersensitivity to DNA damage. Also, intriguingly, tumor cells contain more DSS1 than healthy cells do, and too much of it in breast cancer cells means a poor prognosis. But exactly how DSS1 works wasn’t clear.

Biochemistry professor Patrick Sung, research scientist Weixing Zhao, and their colleagues found that DSS1 acts as a DNA mimic. Normally, BRCA2’s role in DNA repair is to help a molecule called RPA (replication protein A) “hand over” a length of single-stranded DNA (ssDNA) to another key protein. This is no small feat. RPA binds strongly to ssDNA to keep it from degrading. But for repairs to proceed, RPA then has to let go—and, in test-tube studies, it holds onto the DNA so tightly that scientists have long wondered how it ever lets go in living cells.

Sung and Zhao’s team discovered that DSS1 imitates DNA during the repair process. That mimicry essentially fools RPA, causing it to release its grip on the real DNA and attach itself to DSS1. (The discovery was published in the cover story of the July 16 Molecular Cell.) Knowing how DSS1 works may allow scientists to develop drugs to block its function in tumors—which should help to reduce the proliferation of cancer cells.