Page 36 - Hormel Report 2021

Edward H. Hinchcliffe, Ph.D.
“Our research combines the basic science of cell division and cell progression with genetically tractable models of human disease to identify therapeutic vulnera-
bilities and treatment candidates.”
Edward H. Hinchcliffe
36 | THE HORMEL INSTITUTE // Cellular Dynamics
SECTION LEADER / PROFESSOR
UNIVERSITY OF MINNESOTA
My lab seeks to understand the cellular basis for tumorigenesis, in particular pediatric diffuse midline gliomas. We
study cell division, the process where cells sepa- rate duplicated chromosomes into two daughter cells - called mitosis. Mistakes in mitosis lead
to uneven chromosome segregations, which is
a hallmark of cancer progression. Specifically,
we study how single nucleotide changes to DNA (mutations) lead to chromosome missegregation following mitosis. By understanding the molecu- lar mechanisms underlying these cellular defects, we will provide insight into new methods of diag- nosis, prevention and treatment for cancer.
Current research projects:
Chromosome missegregation: Inadvertent chro- mosome missegregation in anaphase generates aneuploid cells, but the proliferation of these cells is normally blocked, because chromosome missegregation also triggers a p53-dependant failsafe that triggers cell cycle arrest in the ensu- ing G1. The molecular mechanisms underlying this trigger are not known.
Recently we have identified a conserved feedback mechanism that monitors the relative position of lagging chromosomes during anaphase via the differential phos- phorylation of the histone variant H3.3 at Ser31. During normal mito- sis H3.3 Ser31 is phosphorylated exclusively at peri-centromeres, which are rapidly dephosphorylat- ed in anaphase. Correlative same cell live and fixed imaging revealed that isolated chromosomes have
hyper-phosphorylated H3.3 Ser31 (pS31) along their arms that persists into G1. Surprisingly, during telophase Ser31 phosphorylation initiates global phosphorylation of H3.3 Ser31 in both reforming nuclei, suggesting both an amplifica- tion step of the aneuploid failsafe, and an expla- nation for why both daughter cells trigger p53 activation in response to a single chromosome missegregation event.
Figure 1: Isolated chromosomes showing the pericentriolar region (green) as a pair of dots.