The Study of Homologous Recombination Defects in Diamond Blackfan Anemia
Abstract
BACKGROUND: Diamond-Blackfan anemia (DBA) is a rare genetic disorder that is characterized by the failure of the bone marrow to produce red blood cells. Some individuals with DBA achieve spontaneous remission (their anemia goes away), whereas others require life-long treatment with steroids or red blood cell transfusions unless they receive a bone marrow transplant. DBA is caused primarily by a change in one of several genes that code for the proteins that constitute ribosomes, which are the structures in cells that take the information in genes to produce proteins. The mostly commonly mutated gene in patients with DBA is called RPS19. It is one of 19 different ribosomal protein genes that may be mutated in DBA. There are a few other genes that may cause DBA or a DBA-like syndrome, but these genes are not associated with the ribosome. In addition to profound anemia, individuals with DBA are at an increased risk of developing a type of cancer of the bone marrow known as myelodysplastic syndrome (MDS). The reason for this is unknown. In the course of our studies on DBA, we discovered that cells, known as lymphoblastoid cells, derived from patients with DBA or cells that are manipulated to have reduced RPS19, mimicking DBA cells, are sensitive to irradiation and have a reduced ability to repair breaks in the DNA. These are novel and quite unexpected findings because the ribosomal proteins mutated in DBA have not been previously associated with the repair of DNA breaks and are thought to cause disease due to changes in the production of proteins by ribosomes. We hypothesize that RPS19 and potentially other DBA-associated ribosomal proteins moonlight as DNA damage response or DNA break repair proteins. We further hypothesize that defects in DNA repair in DBA cells may contribute to the development of MDS. The Specific Aims outlined in our proposal seek to address the first set of critical questions in this new area of research such as: How is RPS19 recruited to DNA breaks and how does its recruitment influence the association of other DNA damage response or repair proteins? Are defects in the DNA damage response or DNA break repair characteristic of all DBA genetic types or just a subset? And lastly, are the defects in the DNA damage response or DNA break repair associated with reduce RPS19 observed in bone marrow stem cells, the key cell type in the development of MDS? INNOVATION: The proposed research is conceptually innovative because it investigates for the first time a role for ribosomal proteins associated with DBA in how cells respond to breaks in DNA, which are among the most dangerous types of DNA lesions. IMPACT: By studying this novel role for RPS19 and other DBA-associated ribosomal proteins, we will open an avenue for future investigation regarding the development of MDS/AML in patients with DBA. Moreover, it may suggest that certain chemotherapy drugs that are effective in cancers that have defects in the same type of DNA repair as DBA cells may be a treatment option for patient with DBA who develop MDS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110415
Entities
People
- Alison A Bertuch
Organizations
- Baylor College of Medicine
- United States Army