DNA repair protein may lead to personalized cancer therapy

June 12, 2013 | by

Understanding how cells repair DNA damage is key to revealing the role of BRCA1 and other tumor suppressors and to overcoming chemotherapy resistance in cancer. City of Hope research just published in Nucleic Acids Research sheds light on this topic and could lead to improved therapies.

Shattered DNA double helix

City of Hope research is helping scientists understand how cells repair damaged DNA. The work may lead to improved cancer therapies.

Principal investigator David K. Ann, Ph.D., an associate professor in the Department of Molecular Pharmacology, explains the significance of this paper “HP1 promotes tumor suppressor BRCA1 functions during the DNA damage response.”

What’s the main finding of this study?
In this study, we found that HP1, a protein that builds heterochromatin (a tightly packed and transcriptionally inactive region in our genome), is involved in the repair of DNA double-strand breaks (DSBs). The three subtypes, HP1α, β and γ, are equally important and promote the recruitment of a tumor suppressor, BRCA1, to the sites of DSB for error-free homologous recombination (HR) repair. In addition, HP1 also enhances BRCA1 function to activate G2/M checkpoint that allows time for repair.

Our findings demonstrate a novel role of HP1 in selecting for a faithful DSB repair pathway and activating proper DNA damage response to promote genome stability through regulating BRCA1.

Three major findings:

  • HP1 plays an active biological role in regulating DNA damage response (DDR) signaling and homologous recombination but not nonhomologous end joining (NHEJ) repair.
  • All three HP1 isotypes (HP1α, β and γ) are important, but not redundant for these DDR functions.
  • The dynamic interaction of HP1 with chromatin, BRCA1, 53BP1 and other DDR factors may provide a novel molecular mechanism for the choice of DNA repair pathway and the cell’s fate in response to DNA damage.

What kind of impact do you expect the study findings to have?
While mutations in BRCA1 are highly associated with breast and ovarian cancer predisposition, it accounts for only 5 to 10 percent of total breast cancer cases. Our results show that cells with compromised HP1 expression fail to execute regular BRCA1 function in response to DNA damage, thereby exhibiting “BRCAness,” suggesting that the level of HP1 may also be correlated with tumorigenesis and disease progression. Therefore, HP1 could serve as a biomarker, in addition to BRCA1/2, for predicting the risk of developing breast cancer and to maximize the therapeutic prospective for a subset of breast cancer patients to achieve personalized medicine.

What does this publication mean to you?
With respect to the clinical relevance of our findings, the BRCA1 gene is frequently mutated in familial breast and ovarian cancers. However, the tumor suppressor functions of BRCA1 can also be impaired by other mechanisms, including the one reported in this manuscript. This loss of BRCA1 function is associated with the loss of HR repair pathway.

Conceivably, reduced HP1 expression could promote tumorigenesis by impairing the formation of BRCA1 foci at DNA breaks, leading to loss of the error-free HR repair pathway. Instead, 53BP1 would be recruited to the breaks, which would lead to activation of the error-prone NHEJ pathway for repair, increasing the incidence of mutations, genomic instability and cancers. Moreover, dysregulation of DDR often enhances the response to anti-cancer therapies that are DNA damaging reagents.

Therefore, we believe our study will make important contributions not only to the understanding of heterochromatin biology and its involvement in different cellular responses to DNA damage, but also to cancer research and, potentially, cancer therapy.

The research team included Assistant Research Professor Young-Ho Lee, Ph.D., and former City of Hope graduate student Jenny Kuo, Ph.D., in collaboration with Jeremy Stark, Ph.D., associate professor of radiation biology, and Hsiu-Ming Shih, Ph.D., of the Institute of Biomedical Sciences, Academia Sinica, in Taipei, Taiwan, Republic of China.

This work was supported by National Institutes of Health grants R01DE10742, R01DE14183 and R01CA120954.