RTEL1 and Genome Stability
Abstract
Cell division is the process of producing two identical cells from the original parent cell. During every cell division our DNA, which is contained within 23 chromosomes, must be replicated without errors to ensure the correct transfer of our genetic material. A network of proteins that detects and repairs errors controls the delicate task of replicating our chromosomes with complete fidelity. If errors, also known as mutations, cannot be repaired, DNA damage response pathways ensure that the damaged cell is eliminated. If mutations are passed on to the newly replicated cells, this can lead to severe outcomes such as cancer and premature aging. Essentially the DNA damage response pathways protect our healthy cells from turning into cancerous ones. For this reason, it is not surprising that most mutations associated with cancer predisposition are directly or indirectly involved in DNA repair activities. However, the detailed mechanism by which our DNA is protected and our cells are prevented from becoming cancerous is not fully understood. Working at a world-renowned cancer center, I have exposure to patients in great need of the advancement of cures for their specific diseases. Two patients treated at Memorial Sloan Kettering Cancer Center (MSKCC) have revealed a novel mutation in a protein called Regulator of Telomere Elongation Helicase 1 (RTEL1). The RTEL protein is involved in maintaining the integrity of our DNA and is necessary for the complete replication of our chromosomes. These individuals, from two different families, shared an amino acid substitution of RTEL1 argenine1264 to histidine and presented with Hoyeraal-Hreidarsson syndrome, a severe variant of the inherited bone marrow failure syndrome dyskeratosis congenita (DKC). We have found that the Rtel1R1264H allele is a founder mutation in the Ashkenazi Jewish population, present at a frequency of 1% among Ashkenazi Jews. Thus, understanding the mechanisms underlying the Rtel1R1264H phenotype has the potential for immediate impact on clinical practice, and in the longer term, for understanding the molecular basis of myelodysplastic and bone marrow failure syndromes which are among the Fiscal Year 2015 (FY15) Peer Reviewed Cancer Research Program (PRCRP) topic areas. Furthermore, DKC patients have a 200-fold increased risk of developing acute myeloid leukemia. The relevance of this proposal extends beyond the bone marrow, as RTEL1 mutations, are also associated with increased risk of brain and colorectal cancers, which are also listed as FY15 PRCRP topic areas. Unfortunately, the original patients are now deceased, so analyses have been restricted to a single skin sample. Accordingly, I will use genetically engineered mice that mimic the identical mutation observed in the patients. These mice thus constitute a novel model that will allow us to assess disease progression invasively in controlled cohorts of affected animals to allow examination of the mechanisms of premature aging, bone marrow failure, and malignancy associated with RTEL1 mutation. The goal is to understand how mutations in RTEL1 lead to severe bone marrow failure and cancer. This research is applicable to active duty military personnel and their families, which may directly be suffering from cancer or myeloid dysplastic syndromes either directly or as a result of treatment for another condition. I also aim to understand how RTEL1 functions in the cells. This protein has only been studied by a handful of labs, and the understanding of RTEL1 s biochemical and biological functions remains largely unknown. I will use human patient and mouse cell lines as well as purified proteins to help clarify the role of RTEL1 in the cells. In addition, I will use a comprehensive approach known as mass spectrometry to find relevant proteins and pathways in which RTEL1 plays a role. The data obtained from my proposal will directly illuminate the mechanisms underlying the pathologies in the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610218
Entities
People
- Fiorella Ghisays
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army