Study Finds Excess Production of RNF168 Protein May Spur Development of BRCA-Mutated Cancers

“Our work describes a strategy that many BRCA1 mutant cancers use to survive and grow,” said John J. Krais, PhD, a postdoctoral associate in the lab of associate professor Neil Johnson, PhD. Krais and Johnson are lead authors of the study.

PHILADELPHIA (March 26, 2020)—In a recent study, researchers at Fox Chase Cancer Center concluded that overproduction of a protein called RNF168 may contribute to the development of BRCA-mutated cancers.

BRCA1 and BRCA2 are tumor suppressor genes that help repair DNA. Mutations in these genes are the strongest known genetic risk factor for breast and epithelial ovarian cancer. It is estimated that 55 percent to 65 percent of women with the BRCA1 mutation will develop breast cancer before age 70; an estimated 45 percent of women with a BRCA2 mutation will develop breast cancer by age 70.

Loss of BRCA1 activity and the ability to properly repair DNA damage fosters an environment for the development of cancer. RNF168 allows cells to maintain a DNA repair pathway that stops working in BRCA1-mutant cancer cells.

“In this study, we further explore the function of RNF168 and describe a previously unknown role for RNF168 in response to DNA damage that arises during cell replication in BRCA1-mutant cells,” said John J. Krais, PhD, a postdoctoral associate in the lab of associate professor Neil Johnson, PhD, in the Molecular Therapeutics program. Krais and Johnson are lead authors of the study.

Neil Johnson, PhD

According to their research, when there is an absence of BRCA1, excessive RNF168 expression may drive break-induced replication and contribute to mutational characteristics seen in BRCA1-mutated cancers. Break-induced replication is a pathway that repairs certain types of DNA breaks but is highly mutagenic.

Although the study has expanded their understanding of RNF168 biology, Krais said more research is needed. He said they are seeking to understand how cells regulate levels of expression, what additional functions RNF168 performs, and how this pathway can be targeted for the development of new cancer drugs.

“We are very interested in how RNF168 controls the synthesis and repair of DNA during the development of cancer. In addition, our ongoing work is aimed at uncovering cofactors that contribute to the survival and growth of BRCA1-mutant cancer,” said Krais.

The study, “Ectopic RNF168 Expression Promotes Break-Induced Replication-Like DNA Synthesis at Stalled Replication Forks,” was published in the journal Nucleic Acids Research.

Fox Chase Cancer Center (Fox Chase), which includes the Institute for Cancer Research and the American Oncologic Hospital and is a part of Temple Health, is one of the leading comprehensive cancer centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase is also one of just 10 members of the Alliance of Dedicated Cancer Centers. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence six consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.

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