A recent research study conducted by University of Pittsburgh and UPMC Hillman Cancer Center scientists revealed that an enzyme known as PARP1 plays a significant role in the repair of telomeres, which are DNA sequences that safeguard the ends of chromosomes. The study suggests that interfering with this process can result in the shortening of telomeres and genomic instability, potentially leading to the development of cancer.The focus of the study is on genome surveillance, which involves detecting breaks or damage in DNA and adding a molecule called ADP-ribose to specific proteins. This serves as a signal to attract other proteins that can fix the damage. The recent findings, which have been published in Nature Structural & Molecular Biology, indicate that PARP1 also plays a role in telomeric DNA repair. This discovery opens up new possibilities for understanding and enhancing cancer therapies that target PARP1. According to Roderick O’Sullivan, Ph.D., an associate professor of molecular pharmacology at Pitt and an investigator at UP, the previous belief that ADP-ribosylation at DNA was not possible has been challenged by recent research.MC Hillman emphasizes the significance of PARP1 as a crucial focus for cancer research. Previously, it was believed that drugs targeting this enzyme only affected proteins. However, it has now been discovered that PARP1 also modifies DNA, leading to the potential to target this aspect of PARP1 biology to enhance cancer treatments. In healthy cells, PARP1 plays a crucial role in repairing genomic lesions that occur naturally during DNA replication. However, BRCA-deficient cancers, such as many breast and ovarian tumors, heavily rely on PARP1 as they lack other DNA repair pathways.they lack a protein called BRCA, which is responsible for controlling homologous replication, a highly effective form of DNA repair.
“Cancer cells that are unable to produce BRCA proteins become reliant on alternative repair pathways that involve PARP1,” explained O’Sullivan. “By inhibiting PARP1, which is the mechanism of action for several approved cancer drugs, we essentially leave the cancer cells with no available repair pathway, leading to their death.”
While the role of PARP1 in ADP-ribosylation of proteins was discovered approximately 60 years ago, O’Sullivan and his collaborator, Ivan Ahel, Ph.D., professor in the Sir William Dunn School of Pathology at the University of Oxford and an expert in the field, have shed new light on this process.PARP1 had a suspicion that there was more to uncover about this particular enzyme and its role within cells.
O’Sullivan and his team, under the leadership of Anne Wondisford, Ph.D., a graduate student in Pitt’s Medical-Scientist Training Program, initially conducted a comparison between normal human cells and those lacking in PARP1. Through the use of specialized antibodies that adhere to ADP-ribose and telomere-specific probes, they discovered that ADP-ribose attaches to telomeric DNA in regular cells but not in PARP1-deficient cells, indicating that this enzyme is responsible for the ADP-ribosylation of DNA.
Following this, they conducted a comparison between normal cells and those lacking another enzyme known asTARG1, a protein that removes ADP-ribose, plays a role in the accumulation of ADP-ribose at telomeres when it is absent. This accumulation leads to the disruption of telomere replication and premature telomere shortening. In order to demonstrate that these telomere defects were a result of telomeric DNA modification, O’Sullivan and his team introduced bacterial enzymes with similar functions to PARP1 into human cells. “We used a guidance system to direct the enzymes to add ADP-ribose only at the telomeres and nowhere else in the genome,” said O’Sullivan. “We found that if we load telomeres with ADP-ribose, their integrity is dramatically impaired, and it can kill the cell within days.”
O’Sullivan suggests that ADP-ribose may impact telomere integrity by disrupting shelterin, a protective structure that guards telomeres. However, further research is necessary to validate this hypothesis.
“Targeting PARP1 has been highly effective in cancer therapy, but some patients develop resistance to PARP1 inhibitors,” O’Sullivan stated. “I am enthusiastic about this study because it has unveiled new insights into PARP1 biology, opening up a plethora of new questions that could potentially aid in the development of innovative approaches to target PARP1 or refine existing therapies. We are just beginning to unravel something exciting, and there is a multitude of possibilities ahead.”
The research team at the University of Pittsburgh and other collaborating institutions, including Columbia University, the University of Sydney, and the University of Oxford, conducted a study on the impact of telomere dysfunction on the development of cancer. The study, funded by various organizations including the National Institutes of Health and the Wellcome Trust, involved researchers such as Sandra Schamus-Haynes, Ragini Bhargava, Patricia Opresko, Junyeop Lee, Jaewon Min, Robert Lu, Hilda Pickett, Marion Schuller, and Josephine Groslambert. The findings of the study suggest that telomere dysfunction plays a significant role in cancer development and provide valuable insights for further exploration in this field.
The research was supported by grants from e (813369), Cancer Research UK (C35050/A22284), Medical Research Future Fund (2007488) and the Biotechnology and Biological Sciences Research Council (BB/R007195/1 and BB/W016613/1).
