DNA Housekeeping Proteins May Also Prevent Cancer

Date: May-06-2013Scientists once thought BAF proteins confined their activity to cellular housekeeping. But then they discovered these complexes do more
than help package and maintain DNA in cells: it seems they also suppress tumor development in many types of tissue. Now a new study from
Stanford University School of Medicine in the US finds BAF proteins are mutated in about one in five human cancers.

Senior author Gerald Crabtree, who is also of the Howard Hughes Medical Institute in Chevy Chase, Maryland, and colleagues, write about their
findings in a paper published online in Nature Genetics on 5 May.
BAF Help Package DNA
BAF is a complex of proteins that are known as chromatin-regulatory complexes. They work to keep DNA tightly packed inside cells, while also
allowing access for switching genes on and off and to allow copying. The enormity of this task is astounding, as Crabtree who is also a
member of the Stanford Cancer Institute, explains:

"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."
BAF Complexes As Tumor Suppressors
The team at Crabtree's lan has been investigating BAF complexes for many years. Nearly 20 years ago, they revealed that complexes of this type
were likely to be tumor suppressors.

More recently, in the journal Nature, they reported that switching subunits in the BAF complexes can
transform human fibroblasts to neurons, suggesting they also play an instructive role in cell development, and possibly, cancer.

In this latest study, they show that BAF complexes "are mutated in nearly 20 percent of all human malignancies thus far examined," says
Crabtree.

The results also show that the mutations have a broad reach, comparable to that of another well-known tumor suppressor, p53.

"Although we knew that this complex was likely to play a role in preventing cancer, we didn't realize how extensive it would be," says co-first
author and postdoctoral scholar Cigall Kadoch.
Patterns of BAF Mutations Seem to Precede Certain Cancers
For the study, Crabtree and colleagues brought together biochemical experiments with data mined from 44 previous studies. The work would not
have been possible without the ability to apply highly accurate genome-wide DNA sequencing technology to individual human tumor
samples.

The team discovered that certain patterns of mutations in the subunits of the BAF complexes seem to precede specific cancers. For example, one
pattern suggests ovarian rather than colon cancer will follow.

When they found that in some cases even just one mutation in a subunit was enough to trigger cancer, they realized how important a role BAF complexes
must play in tumor suppression.

Kadoch says they found one example of this in a "a type of mutation called a chromosomal translocation in the gene encoding one of these newly
identified subunits, SS18, is known to be the hallmark of a cancer called synovial sarcoma."

"It is clearly the driving oncogenic event and very often the sole genomic abnormality in these cancers," she adds.
19.6% of All Human Tumors Showed at Least One BAF Mutation
The researchers identified 7 proteins previously unknown to be BAF components. They then looked at previous studies that had sequenced DNA
from human tumors to find out how often any members of the complex were mutated.

They were surprised to find that 19.6% of all human tumors showed a mutation in at least one of the subunits in the complex. Also, for certain
cancers, like synovial sarcoma, every analyzed tumor sample had a mutation in a BAF subunit.

The team concludes that when unmutated, BAF complexes must play a key role in preventing cancer in many types of tissue:

"Thus, proper functioning of polymorphic BAF complexes may constitute a major mechanism of tumor suppression," they write.
Further Questions to Explore
The team now wants to find out exactly how the mutations interfere with the complex's ability to suppress tumors. For instance, do they promote
cancer by interfering with the cell cycle? Or do they block the way the complex is positioned on the DNA?

The study is another example of some of the surprising findings that have been published recently about the role of mutations in cancer. In
February 2013, researcher at MIT revealed how they found that just as some mutations in the genome of cancer cells actively spur tumor growth, there are
also some that slow it down or even stop it.

Written by Catharine Paddock PhD

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