In a novel combination of biochemical experimentation and data mining, Stanford researchers and postdoctoral scholars Cigall Kadoch, PhD, and Diana Hargreaves, PhD, have identified a large protein complex that appears to be significantly involved in cancer development in humans.
The multisubunit is a member of a family of chromatin-regulatory complexes that keep DNA tightly packed in a cell's nucleus. Originally thought of as a kind of housekeeping, or maintenance, protein in the cell, it's now becoming apparent that these complexes are really important in development and cancer.
Kadoch, working in the laboratory of developmental biologist Gerald Crabtree, MD, used biochemical techniques to identify seven previously unidentified members of the complex, which is called BAF (or mSWI/SNF). She and Hargreaves then analyzed 44 pre-existing studies that detailed the DNA sequences of primary human tumors of all types. They calculated the likelihood that any protein component of the large group was mutated. (The approach varies from others that analyze the mutation rates of individual proteins.)
As described in our release:
The results, once the newly discovered members were included, were surprising: 19.6 percent of all human tumors displayed a mutation in at least one of the complex's subunits. In addition, for some types of cancers (such as synovial sarcoma), every individual tumor sample examined had a mutation in a BAF subunit. The results suggest that the BAF complex, when unmutated, plays an important protective role against the development of cancer in many different tissues.
Crabtree, who is also a Howard Hughes Medical Institute investigator, described his lab's long-standing interest in BAF and other similar protein complexes:
Somehow these chromatin-regulatory complexes manage to compress nearly two yards of DNA into a nucleus about one one-thousandth the size of a pinhead. And they do this without compromising the ability of the DNA to be replicated and selectively expressed in different tissues - all without tangling. In 1994 we reported that complexes of this type were likely to be tumor suppressors. Here we show that they are mutated in nearly 20 percent of all human malignancies thus far examined.
The work was published yesterday in Nature Genetics. The researchers are now working to understand exactly how the mutations they've observed affect the function of the BAF complex.
Previously: Dumb, dumber and dumbest? Stanford biologist suggests humans on a downward slide and New clues arise in pancreatic cancer from Stanford researchers
Photo of (left to right) Cigall Kadoch, Gerald Crabtree and Diana Hargreaves, by Nathaniel Hathaway