Dr. Noa Lamm-Shalem, Sydney Medical School, Sydney University. Children’s Medical Research Institute, Sydney
17/01/2022 13:00

Title: Filamentous actin drives nuclear architectural changes to maintain genome stability


Abstract: Cell proliferation requires efficient and accurate DNA replication. The complexity of replication, however, renders genome copying susceptible to endogenous and exogenous threats. Any process hindering replication is referred to as “replication stress,” and the cellular processes that countervail replication threats are the “replication stress response”. Most of the genome instability that drives oncogenesis results from replication stress, and consequently, cancer cells typically suffer from endogenous replication stress and are susceptible to replication stress response challenges.

Actin is a cytoskeletal protein that polymerizes from monomeric to filamentous form(F-actin) to provide cells with mechanical support, transport pathways, and a driving force for movement. While actin is traditionally considered a cytoplasmic protein, nuclear actin polymerization was recently identified to contribute to various nuclear functions.

I employed live-cell and super-resolution imaging, chromatin fiber analysis, biochemistry, and cell and molecular biology to discover a novel replication stress response pathway where polymerization of nucleus-specific filamentous actin (F-actin) promotes replication stress repair. In this pathway, nuclear F-actin cables increase nuclear volume and sphericity and enhance the mobility of replication stressed chromatin. This includes directed movement of stressed replication foci along F-actin towards the nuclear periphery where replication stressed loci interact with nuclear pore complexes to promote their repair. These data substantially broaden our understanding of the nucleus as a dynamic environment shaped by nuclear actin forces. This is a conceptual advance in nuclear biology only beginning to be explored.

Host: Prof. Benjamin Podbilewicz