DNA Repair Defects Emerge as a New Category for Anticancer Therapies

Jane de Lartigue, PhD
Published: Friday, Dec 02, 2016
A coordinated network of signaling pathways works to protect the cell from the toxic effects of DNA damage. Its vital importance to cellular integrity is underscored by the fact that hereditary mutations in DNA repair genes dramatically increase cancer risk, as exemplified by the breast cancer susceptibility (BRCA1/2) genes, which encode proteins involved in the homologous recombination (HR) repair pathway.

An increasing appreciation of the mechanisms of HR-based DNA repair and the extraordinary sensitivity of BRCA1/2-mutant cells to DNAdamaging conventional therapies have also fueled the development of targeted therapies that exploit HR deficiency.

The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza) became the first approved drug based on the concept of targeting HR deficiency in cancer in December 2014. Since then, the identification of BRCA1/2 mutations and other HR pathway mutations that confer BRCAness in a range of other tumor types suggests that this strategy could prove to be the jumping off point for a new treatment paradigm for cancer.

Coping with DNA Damage

The cells in our body come under frequent assault from a wide variety of stressors, from both the internal and external environments, that can cause several different types of structurally distinct DNA damage. In order to cope, cells have evolved a complex signaling network, known as the DNA damage response (DDR), that plays a vital role in detecting and repairing DNA damage or, if the damage is irreparable, in initiating cell death to clear the damaged cell from the body.

The most common type of DNA damage, with tens of thousands occurring in each cell every day, are single-strand breaks (SSBs), affecting just one strand of the DNA double helix. They are usually rapidly and efficiently repaired, primarily through the base excision repair (BER) pathway, and thus are not particularly toxic. In some cases, because of damaged repair pathways or errors in the repair process itself, SSBs are allowed to accumulate, resulting in the formation of a double-strand break (DSB), where the damage impacts both strands of the DNA helix. These are far more toxic to the cell and their effective repair is vital for cell survival.

One of the major pathways of DSB repair is HR, a mostly error-free process that uses a homologous DNA template to repair the damaged DNA exactly as it was. The template used is most commonly the sister chromatids; therefore, HR is mostly limited to the S and G2 phases of the cell cycle when these are more easily accessible. HR involves 3 main steps: the DNA is resected to generate single-stranded DNA ends, a step that is dependent on the activity of a complex of 3 key proteins, MRE11, NBS1, and RAD50 (known collectively as the MRN complex) and replication protein A (RPA) binds to the resulting DNA ends; RAD51 then forms filaments made up of nucleic acids and proteins on the RPA-coated strands, which seek out homologous sequences within the sister chromatids; using the homologous DNA template, RAD51 performs a recombinase reaction to repair the damaged DNA.

A Hallmark of Cancer

Unrepaired damage can impact the integrity of the genome, creating the genomic instability that is a hallmark of malignant cells and leading to accumulation of further genomic aberrations that support cancer cell growth and survival. It is unsurprising, therefore, that many different types of malignancies display DNA repair defects.

The most notorious are mutations in the BRCA1 and BRCA2 genes, which are linked to a dramatic increase in the risk of hereditary breast and ovarian cancers. Overall BRCA1/2 mutations are present in 5% to 10% of breast cancers and 10% to 15% of ovarian cancers, but the prevalence is highest in the most aggressive forms of these diseases, triple- negative breast cancer (TNBC) and high-grade serous ovarian cancer, respectively.

Mutations in the BRCA1/2 genes are believed to cause cancer in several different ways, but the best understood mechanism is the role that the proteins they encode play in the HR pathway of DNA DSB repair, predominantly in regulating the recruitment and function of the RAD51 protein.

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Online CME Activities
TitleExpiration DateCME Credits
Cancer Summaries and Commentaries™: Update from Chicago: Advances in the Treatment of Breast CancerJul 31, 20181.0
Community Practice Connections™: Personalized Sequencing in Castration-Resistant Prostate Cancer: Bridging the Latest Evidence to the Bedside in Clinical ManagementAug 25, 20181.5
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