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

Award Number: F31CA310394
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $50,114 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	001	1	4/17/2026	NEW	$0
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	1	4/17/2026	NEW	$50,114
														Subtotal = $50,114

Grand Total All Awards = $50,114

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

Award Number: F31CA310394

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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