Molecular modulators of radiation-induced chromosome instability and hematopoietic damage

Abstract The hematopoietic system is one of the organ systems most vulnerable to radiation induced short- and long- term damage. Efficient recovery from pathological or medically induced bone marrow failure is dictated by the intrinsic sensitivity of the hematopoietic stem cell and the bone marrow environment niche. Identification of molecules that affect hematopoietic recovery is essential to the development of novel medical countermeasures against radiation damage. Our preliminary studies suggested that loss of even a single copy of Bccip confers hypersensitivity of mice to radiation-induced hematopoietic syndrome and lymphomagenesis, and the recruitment of BCCIP to DNA damage sites are dependent on PARP1. We hypothesize that Bccip haploinsufficiency can sensitize the hematopoietic stem cells to radiation killing, impair the long-term competency of stem cell to reconstitute the hematopoietic system, and/or affect the bone marrow niche?s capacity to nourish hematopoiesis. In Aim 1, a series of long-term and short-term experiments will be used to determine whether Bccip haploinsufficiency enhances the killing of hematopoietic stem and progenitor cells, impair stem cells? capacity to reconstitute the bone marrow, and diminish the ability of bone marrow niche to nourish the hematopoiesis. We also hypothesize that Bccip haploinsufficiency alters the bone marrow progenitor cell susceptibility to tumor initiation and subsequent tumor progression. In Aim 2, we will test this hypothesis by examining the tumor clonality and defining the landscapes of chromosome rearrangements in the tumors formed in wild type and Bccip haplo-insufficient mice using newly developed genomic and computational approaches. In Aim 3, we will determine the PARylaiton dependent mechanism by which BCCIP is recruited and retained at the DNA damage sites. Completion of these studies will elucidate a unique role of Bccip in modulating hematopoiesis after radiation damage and in suppressing radiation-induced tumorigenesis.