Speaker: Pam Geyer, Professor - Department of Biochemistry, The University of Iowa

Title: Shaping of nuclear structure during mitosis impacts stem cell survival

Abstract: Prominent changes in nuclear structure accompany physiological aging and many disease states. I have been interested in how such changes in nuclear structure cause declining function. Nuclear structure depends on the nuclear lamina (NL), a protein network that lines the inner nuclear membrane and builds contacts with the genome to regulate transcription, replication and DNA repair. Mutation of genes encoding NL proteins cause a remarkable spectrum of age-enhanced human diseases, known as laminopathies that include accelerated aging disorders such as Hutchinson Gilford and Nestór-Guillermo progeria syndromes. Laminopathies result from a failure to maintain adult stem cell populations. Mechanisms of stem cell loss are poorly understood. We have identified a functional link between a NL LEM-domain (LEM-D) protein and stem cell homeostasis in adult germline stem cells (GSCs) in Drosophila. We established that NL deformation activates a non-canonical pathway leading to DNA damage and stem cell death. NL function and stem cell longevity depend upon Otefin, a LEM-D protein that links the genome to the NL through association with Barrier-to-autointegration Factor (BAF), the protein defective in Nestór-Guillermo progeria. Without Otefin, the NL becomes distorted, resulting in activates two checkpoint kinases canonically that are well known for roles in the DNA damage pathway, the sensor kinase ATR and its downstream effector kinase Checkpoint kinase 2 (Chk2). Surprisingly, we found that activation of these kinases does not depend on DNA damage. Our studies have advanced the nuclear lamina field. Of these, the two most notable contributions include 1) overturning a highly cited model for Otefin and NL function in GSCs (Jiang et al., 2008, Dev. Cell 14: 494.) and 2) discovery of a novel NL checkpoint. How NL dysfunction triggers ATR/Chk2 activation is unknown and forms the basis of this proposal.