Saturday, November 23, 2024
11/23/2024
PROJECT SUMMARY/ABSTRACT The goal of this proposal is to determine the mechanistic basis for mutational processes that drive very rapid evolution of cancer genomes. One process causing mutation bursts is chromothripsis, massive rearrangement of one or a few chromosomes occurring within a single cell division. Under this grant, my group established a general mechanism for chromothripsis. This work was enabled by our development of a novel technical approach, the ability to combine live cell imaging, same cell isolation, and single cell whole genome sequencing (Look-Seq). Chromothripsis originates from abnormal structures of the nucleus—micronuclei (MN) or chromosome bridges. We identified a defect in nuclear envelope assembly on chromatin that lags within the mitotic spindle. This results in nuclear envelope (NE) fragility and spontaneous NE rupture. Exposure of MN chromatin to the interphase cytoplasm leads to extensive DNA damage, which is followed by a second wave of DNA damage upon entry into mitosis. The first two aims of this proposal address the mechanisms leading to chromosome fragmentation that is the basis for chromothripsis. First, building on preliminary data we will test the hypothesis that exposure of MN chromatin to the interphase cytoplasm causes DNA damage via an aberrant pathway of DNA base excision repair. Second, we propose hypothesis driven and unbiased approaches to identify the mechanism of MN chromosome fragmentation in mitosis. Finally, we address the mechanism of another poorly understood, common cancer genome catastrophe termed chromoplexy.
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