Passing the BRCA1 Baton: Possible target of anticancer protein identified (DNA damage; Cancer)
Authors: Davenport R. John 
Published: August 2003

Unlike some companies, cells house control systems that keep unrestrained activities in check. New work hints at how a gene implicated in breast cancer--
BRCA1
--fits into the power structure. Although the results need to be confirmed, the study helps establish BRCA1's place in the web of proteins that governs cell proliferation.

When cells' genetic material gets marred, they normally stop reproducing to fix it; unless repaired, the dinged-up DNA can cause cancer. Cell culture studies have indicated that malfunctioning BRCA1 disrupts the ability of cells to recognize DNA damage and halt division in response. According to recent experiments, BRCA1 is activated by a protein called
ATM
. Flawed ATM leads to a disease caused by defects in DNA repair that allow cancer to run rampant (see Genetically Altered Mice:
tg1
,
tg2
, and
tg3
). But no one has pinpointed the proteins to which BRCA1 passes the DNA damage signal.

To hunt down BRCA1's targets, Yarden and colleagues exposed two types of cultured cells--breast cancer cells that naturally lack BRCA1 and the same cells engineered to produce it--to damaging radiation and analyzed their behavior. After the treatment, cells that produced BRCA1 conducted themselves properly: They halted just before they started mitosis, a process in which a cell divides in two. Cells that lacked BRCA1, however, continued to career down the cell-division pathway.
Proteins called Chk1 and Chk2 broadcast signals that delay mitosis until damage can be fixed, and the researchers wondered whether BRCA1 activates either of these molecules. Both proteins get jolted into action when they receive phosphate groups, so the group tested whether Chk1 and Chk2 carried this chemical group. When cells were irradiated, Chk2 became phosphorylated regardless of whether BRCA1 was around. Chk1, on the other hand, received a phosphate only with BRCA1 present, suggesting that BRCA1 was responsible for the addition. Further experiments showed that Chk1 also required BRCA1 to add phosphates to its own protein target, supporting the notion that BRCA1 prods Chk1 to do its job. Next, the researchers tested whether BRCA1 and Chk1 make contact with each other. Antibodies that grab BRCA1 from a mix of cell contents pull out Chk1 as well. Together, the results suggest that BRCA1 transmits a DNA damage signal to Chk1.
The study narrows "where in the DNA damage response signaling pathway BRCA1 might actually be functioning," says radiation oncologist Steven Leadon of the University of North Carolina, Chapel Hill. But other scientists are skeptical. The data don't nail down the link between BRCA1 and Chk1, says Stephen Elledge, a cell biologist at Baylor College of Medicine in Houston, Texas. He would like to see more experiments proving that the group measured Chk1 activity instead of the activity of another enzyme with overlapping abilities. Eager to pinpoint BRCA1's target, Elledge adds, "If it turns out to be real, it will be really interesting."
--R. John Davenport

R. I. Yarden, S. Pardo-Reoyo, M. Sgagias, K. H. Cowan, L. C. Brody, BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage.
Nature Genet.
, 11 February 2002 [e-pub ahead of print].
[Abstract]
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