09/09/2013 - Institutional news
Researchers from the IMIM (Hospital del Mar Medical Research Institute) have proven that protein PARP2 plays a key role in maintaining the integrity of the genome of blood stem cells, also known as haematopoietic cells. These results may prove useful to design new drugs and to improve therapeutic strategies based on radiotherapy and chemotherapy.
In human cells, cell activities and environmental factors may damage DNA causing up to a million lesions in a cell each day. These lesions can cause mutations that are potentially harmful for the cell’s genome, affecting the survival of “daughter cells”. The haematopoietic system dealing with the formation, development and maturation processes of blood cells is maintained thanks to a small number of stem cells in the bone marrow that are renewed indefinitely during life and lead to the creation of parent cells and all mature blood cells. An appropriate response to the damaged DNA is essential for the normal functioning of these cells and to avoid programmed cell death or the development of diseases such as cancer.
This study, lead by Dr. José Yélamos, the coordinator of the IMIM Poly (ADP-ribose) Polymerases Group and published in the Blood journal, is part of the group’s general research line with the aim of clarifying the specific functions in the response to the damage to the DNA of a group of proteins within the PARP family (PARP-1, PARP-2 and PARP-3), which are activated as a response to this alteration and assess their usefulness as therapeutic targets for cancer. Even if today there is a great interest in the use of anti-cancer compounds that act on PARP-family proteins, until now all available inhibitors used in clinical trials lack the specificity for each of the proteins in this family.
According to José Yélamos “The specific inhibition of PARP-2 could be useful to increase the sensitivity of cancer stem cells to radiotherapy while the specific inhibition of PARP-1 could reduce the toxicity and avoid failure in bone marrow”.
This study compared the response to DNA damage induced by low doses of radiation in three groups of mice: control mice, PARP-2 deficient mice and PARP-1 deficient mice. Also, double deficient mice were used, meaning PARP-2 and p53 deficient mice, as well as lacking p53 dependent proteins (Noxa and Puma). P53 is a tumour suppressor that is essential to induce the cell’s response to DNA damage, stopping the cell cycle and/or inducing cell death when the damage cannot be repaired. Researchers have shown that p53 deficiency and Puma deficiency avoid bone marrow failure in PARP-2 deficient mice responding to low doses of radiation, whereas Noxa deficiency has no effect.
One of the big challenges in this study is to elucidate the interaction of PARP-2 and the interactions of poly(ADP-ribosylation) mediated by this enzyme with other components in the response to AND damage induced both by exogenous and endogenous factors. Understanding how this response to DNA damage occurs may have important implications for knowing the molecular mechanisms involved in cancer and for indentifying new targets and/or therapeutic strategies.
Article of reference:
“PARP-2 is required to maintain hematopoiesis following sublethal Y-irradiation in mice”. Jordi Farrés, Juan Martín-Caballero, Carlos Martínez, Juan J. Lozano, Laura Llacuna, Coral Ampurdanés, Cristina Ruiz-Herguido, Françoise Dantzer, Valérie Schreiber, Andreas Villunger, Anna Bigas and José Yélamos. Doi:10.1182/blood-2012-12-472845