Abstract

Complexes that physically bridge the two membrane bilayers of the nuclear envelope, termed LINC complexes, mechanically couple chromatin within the nucleus to the cytoplasmic cytoskeleton. Through these physical connections, the cytoskeleton has the ability to affect chromatin dynamics and deliver force onto attached chromatin regions. At the same time, the chromatin acts as a critical physical buffer and anchor point for the cytoskeleton to productively drive nuclear movement without disrupting nuclear structure. Using fission yeast as our model system, we focus on two areas: investigating how the cytoskeleton acts as an input to chromatin biology and defining how chromatin contributes to nuclear mechanics. Recently, we found that persistent DNA double-strand breaks (DSBs) are recruited to the LINC complex. Our data suggests that association of DSBs with the LINC complex facilitates the homology search during repair by homologous recombination, likely by altering the dynamics of DSBs within the nucleus. To complement our in vivo studies, we are developing an in vitro assay to investigate nuclear mechanics using force spectroscopy. Ultimately, using the combination of these approaches, we hope to gain a mechanistic understanding of the interplay between chromatin and the cytoplasmic cytoskeleton.

http://medicine.yale.edu/labs/king/