Recently, researchers have discovered a hot spot for mutations that account for the majority of inherited, late- onset myelodysplastic syndromes (MDS). Individuals with this mutation have a 50/50 chance of developing MDS with rapid progression to leukemia. The prognosis for such patients is favorable. Still, current treatments are limited to standard protocols, without consideration for the offending hot spot mutations. Further, standard protocols suffer from toxicity and poor prognosis after bone marrow transplant. Targeted strategies that focus on the immediate consequences of these hot spot mutations promise to improve outcomes for patients. Such a targeted approach requires a mechanistic understanding of the gene product disrupted by these hot spot mutations. This gene product has recently also been shown to bind an important part of the machinery that excises “introns” (which interrupt our genes), after a gene has been turned on and before its message is translated into protein. We have shown that this important part of this machinery plays a key role, conserved from baker’s yeast to human cells, in proofreading intron excision, to prevent errors that lead to corrupted protein synthesis. The direct, physical interaction between this important part of the machinery and the MDS hot spot gene product implicates a role for this MDS gene product in proofreading intron excision as well. At the same time, the MDS hot spot gene product has been implicated untangling DNA “knots” that can impede cell growth, and MDS hot spot mutations compromise this untangling. The direct, physical interaction between the important part of the intron excision machinery and the MDS hot spot gene product raise the possibility that this important part assists the MDS hot spot gene product in untangling DNA. Regardless, the implication of the hot spot gene in intron excision opens a compelling path for the identification of small molecules that correct defects of the hot spot mutations. Thus, our aims for this grant are to define the functions of the hot spot gene product in intron excision and DNA untangling and to screen for potential therapeutics that reverse the impact of hot spot mutations and improve MDS patient outcomes.