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Kielkopf Lab

URMC / Labs / Kielkopf Lab / Projects

Research Projects

Human life depends on pre-mRNA splicing for cellular viability, differentiation and responses to changing physiology or environment. A major focus of my laboratory is to understand at a molecular level how the splicing machinery identifies sites for excision from gene transcript RNAs, which in turn changes the proteins produced. We have characterized the three-dimensional shapes of human splicing proteins recognizing one another and the gene transcript RNA at high resolution by X-ray crystallography complemented by molecular biology in human cells. Through this research, we identify a network of interactions responsible for recognizing human splice sites. The broader impact of this work for human disease is emphasized by the severe defects in pre-mRNA splicing that accompany most human hematologic malignancies and many metabolic disorders, as well as the dependence of HIV-1 and other complex retroviruses on RNA splicing for infectivity. Specific projects include:

Molecular Recognition During pre-mRNA Splicing

C3The overall goal of this research is to understand how essential ternary complexes of SF1, U2AF65, and U2AF35 splicing factors recognizes 3ยด splice sites and initiates the process of spliceosome assembly.

Learn more about Molecular Recognition During pre-mRNA Splicing

Molecular Actions of Prevalent U2AF1 Mutations in Myelodysplastic Syndromes

4YH8 thumbSpecific mutations in the U2AF1 proto-oncogene, which encodes the U2AF35 protein, are prevalent among patients with hematological malignancies, including 10-12% of patients with myelodysplastic syndrome (MDS) without ring sideroblasts and 8-11% of patients with chronic myelomonocytic leukemia (CMML).

Learn more about Molecular Actions of Prevalent U2AF1 Mutations in Myelodysplastic Syndromes

Structural Control of Human Co-factors for Retroviral Gene Expression

tatSF1Viruses such as HIV-1 use the human machinery to produce its RNA transcripts for protein expression and ultimately genomic replication. How viruses hijack cellular processes through interactions with host macromolecules is a fundamental question in biology and medicine.

Learn more about Structural Control of Human Co-factors for Retroviral Gene Expression