What is the basis for telomere/centromere interchangeability in controlling nuclear envelope breakdown?

National Cancer Institute, Frederick MD

Investigators

Abstract

Project Summary/ Abstract Faultless cell cycle progression resides in the timely coordination of numerous regulatory checkpoints that safeguard chromosome integrity, preventing human diseases such as cancer. We have shown that telomeres and centromeres share a specific job in orchestrating this process. Traditionally, the canonical functions of telomeres and centromeres have been considered mutually exclusive. While both chromosomal landmarks are packaged into heterochromatin and recruit specific nucleoprotein complexes to maintain their identity, they were otherwise thought to be structurally and functionally distinct, with telomeres preventing the degradation and fusion of chromosome termini while centromeres confer attachment of chromosomes to spindle microtubules during nuclear division. Our work led to the unprecedented observation that telomeres and centromeres share the ability to contact the meiotic linker of the nuclear cytoskeleton complex (LINC) complex at the nuclear membrane and trigger the partial nuclear envelope breakdown (NEBD) necessary for meiosis. This telomere-LINC contact is required for the spindle pole body (SPB) to access the chromosomes and confer spindle-chromosome association. We find that centromere-LINC contacts play an analogous role in mitosis, further supporting the notion that chromosomes take part in orchestrating their own nuclear divisions. We are examining the compelling observation that these distinct chromatin regions are endowed with NEBD initiating properties. To address the basis for this phenomenon, Aim 1 establishes a plasmid based recruitment system that allows for the efficient localization of alternate chromatin regions to the LINC complex, to explore the specificity of telomeres and centromeres and what other regions may share NEBD-triggering capability. Aim 2 harnesses the biochemical power of this system and sets up a comprehensive framework to dissect the molecular features of chromatin regions that impart local NEBD. Aim 3 explores the phase-separation properties of telomeres and their role in NEBD. Through a multifaceted approach, the field stands to gain novel insight on the molecular conditions that grant chromosomes the ability to govern cell cycle progression during meiosis and mitosis.