Replication at DNA damage sites highlights Fanconi anemia and breast cancer proteins

HOUSTON – While Fanconi anemia (FA) is a rare and dangerous disease, new laboratory research at The University of Texas M. D. Anderson Cancer Center shows it may lead researchers toward clues in more common diseases, including highly hereditary types of breast cancer.

In a study published in the Sept. 11 issue of the journal Molecular Cell, scientists report that
recruitment of proteins to DNA damage sites is controlled by replication in both FA and BRCA
cancer proteins.

Lei Li, Ph.D, professor in Experimental Radiation Oncology at M. D. Anderson, and corresponding
author of the study, has spent much of his 15-year career studying how the body repairs DNA
damage. He says DNA crosslinks are the most severe type of DNA damage; they’re actually turned
against cancer in certain drugs, including cisplatin.

Answers have been elusive

People with FA, a hereditary disease, are extremely sensitive to DNA crosslinks and at a very high
risk for cancer. How the Fanconi pathway protects cells from DNA crosslinks and whether FA
proteins act directly on crosslinks has remained unclear despite extensive research.

“Our lab has been working for almost 10 years on why FA cells are so sensitive to crosslinking,” Li
said. “We’ve known it must have something to do with how they deal with DNA crosslinks, but this
is the first time we’ve been able to pinpoint a reason for some of them.”

FA involves 13 genes; a mutation in any one of them can cause the disease. Three of the FA genes
recently were found to be identical to breast cancer susceptibility genes BRCA2, BACH1 and
PALB2.

“This led us to begin to examine breast cancer genes, since we thought they might have something
to do with the repair of DNA crosslinkers,” Li said.

Researchers developed a novel genetic technique, eChIP, a chromatin-IP-based strategy, to examine
FA proteins with DNA crosslinks.

“The model scientists have been following for many years is that all 13 genes must work together to
deal with DNA crosslinks, that there must be some kind of cascade or chain reaction,” Li said. “We
developed a new genetic technique to look specifically at what proteins are present at the
crosslinks.”

New method yields answers

Using this new tool, researchers found that all the FA genes are present in the site of a crosslink.
This is the first time FA proteins have been linked directly with DNA crosslinking damage at the
molecular level.

“The surprise is that the breast cancer proteins, although they are present at crosslinks, must have
DNA replication at the crosslinks,” Li said. “If there is a DNA lesion on the genome but no DNA
replication, the canonical FA proteins are used to deal with the damage. The breast cancer-related
FA proteins are taking care of the DNA lesion that stops DNA replication.”

Li said this leads to a new paradigm that there must be two separate subgroups or subpathways
within the 13 FA genes.

“The major implication of this study is that now we have a new working model,” Li said. “This
provides a new direction for future research of breast cancer proteins and DNA damage response in
general.

“Our next step is to continue to look at how FA proteins and the subgroup of breast cancer-related
proteins help protect cells from DNA crosslink damage. And, in a more general sense, how these
cellular mechanisms eventually may help us minimize mutations that ultimately lead to cancer.”

This research was supported by grants from the National Institutes of Health.

Co-authors include Xi Shen, Ph.D., Huong Do, and Woo-Hyun Chung, Ph.D. at M. D. Anderson;
Yongjiang Li, Ph.D., and Weidong Wang, Ph.D., at the National Institute on Aging; Maria Tomasz,
Ph.D., at City University of New York; Johan P. de Winter, Ph.D., at VU Medical Center in The
Netherlands; Bing Xia, B.D., UMDNJ-Robert Wood Johnson Medical School; Stephen J. Elledge,
Ph.D., at Harvard Medical School.

About M. D. Anderson

The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world’s most respected
centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 40
comprehensive cancer centers designated by the National Cancer Institute. For four of the past six years, including
2008, M. D. Anderson has ranked No. 1 in cancer care in “America’s Best Hospitals,” a survey published annually
in U.S. News & World Report.

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