Regulation of membrane-chromatin interactions in mitotic nuclear formation and cancer cell survival

The National Cancer Institute awarded Yale University $100,228 on December 1, 2026, under the Cancer Research Manpower program (CFDA 93.398) to support research training and biomedical career development in cancer research.

Yale will conduct basic research on the regulation of membrane-chromatin interactions during mitotic nuclear formation and their role in cancer cell survival. The project investigates how endoplasmic reticulum membranes and LEM-domain proteins, including LEMD2 and emerin, coordinate with the DNA-binding protein BAF to assemble the nuclear envelope during cell division. The research hypothesizes that LEMD2 cooperates with ER membrane availability to prevent nuclear instability by limiting chromatin-membrane tethering and competing with emerin for BAF binding. Preliminary data show that loss of LEMD2 in cells with excessive ER membranes results in unstable nuclei with frequent membrane invasions and multilobed morphology, characteristic of compromised genomic stability in cancer cells.

Performance occurs in New Haven, Connecticut, with a period of performance from December 1, 2026, through August 31, 2029. The Cancer Research Manpower program supports biomedical training opportunities for individuals pursuing careers in basic, clinical, and prevention research relevant to the National Cancer Program, with awards typically spanning up to five years and renewable for additional periods.

Abstract

As cancer cells proliferate uncontrollably, they often exhibit abnormal nuclei with compromised nuclear integrity, contributing to genomic instability and promoting alterations that enhance cell survival. A critical step in maintaining nuclear integrity during cell division is the proper assembly of the nuclear envelope (NE) at mitotic exit. NE assembly occurs when recycled endoplasmic reticulum (ER) membranes wrap around chromatin to form a continuous nuclear membrane surface. Central to this process is the DNA-binding protein BAF, which crosslinks chromosomes and facilitates membrane- chromatin tethering. LEM-domain proteins, including LEMD2 and emerin, bind to BAF, guiding the ER membranes to enclose the chromatin mass, ensuring proper nuclear formation and maintaining genomic stability. Despite the consensus that proper NE reformation is critical for nuclear integrity, the precise mechanisms by which membrane-chromatin interactions coordinate accurate nuclear formation remain unclear. My project aims to explore how membrane-chromatin interactions during mitosis regulate NE assembly and their role in cancer cell survival. I hypothesize that LEMD2 and ER membrane availability cooperate to enable formation of a singular nuclear surface to prevent nuclear instability. Mechanistically, LEMD2 may prevent defective nuclear membranes by limiting chromatin-membrane tethering during mitosis, primarily by competing with emerin for binding to BAF. In line with my hypothesis, we identified cancer cell lineages with high emerin levels that are selectively dependent on LEMD2. Furthermore, preliminary data shows that unstable NES with frequent membrane invasions generating multilobed nuclei result from loss of LEMD2 in cells with excessive ER membranes. To address my hypothesis, i developed the following aims: aim 1 will investigate how membrane abundance influences NE assembly by using live imaging to monitor NE reformation. This will help US understand how membrane availability affects the timing of nuclear protein accumulation during NE formation. Aim 2 will examine whether LEMD2 competes with emerin to limit chromatin- membrane tethering. This will provide insights into LEMD2 interactions and how IT modulates membrane interactions during mitosis. Aim 3 will assess whether cancer cell lineages with high emerin expression are more sensitive to LEMD2 loss. This will reveal the role of LEMD2 in maintaining nuclear stability in cancer cells with altered nuclear envelope dynamics, possibly through its chromatin tethering function. This research will clarify the role of LEMD2 in NE assembly and its contribution to cancer cell survival, providing potential therapeutic targets and biomarkers for cancers with disrupted nuclear integrity.