Role of nuclear lamins in chromosome ositioning and genome stability

Abstract

Chromosome territories are non randomly organized in the interphase nucleus with gene richchromosomes predominantly localized towards the nuclear interior and gene poor chromosomestowards the nuclear periphery Such an arrangement is conserved across evolution and largelyconserved across cell types In addition gene loci that are orders of magnitude smaller thanchromosome territories are also non randomly organized in the nucleus with transcriptionallyactive genes being 8215 looped out 8216 of their chromosome territories The molecular basis of a nonrandom arrangement in the nucleus is not completely understood Nuclear Lamins are type Vintermediate filament proteins that form a meshwork beneath the inner nuclear membrane Inaddition both A and B type Lamins also show nucleoplasmic pools in the nuclear interior In thisstudy we have investigated the role of Lamin A C and Lamin B2 in the organization ofchromosome territories and genome stability This study was performed in diploid colorectalcancer cells 8211 DLD1 and showed non overlapping functions for nuclear Lamins A C and B2 inregulating genome stability and organization Lamin A C and Lamin B2 knockdown revealedspecific sets of chromosomes that were transcriptionally deregulated Depletion of Lamins A Cand B2 induced aneuploidy in otherwise diploid DLD1 cells as revealed by an increase in thenumber of chromosome territories in the interphase nucleus Aneuploid chromosome territoriesshowed a mislocalization in the interphase nucleus in a sub population of Lamin B2 but notLamin A C depleted cells suggesting a specific role for Lamin B2 in the regulation of spatialpositions of aneuploid chromosome territories Lamin B2 depletion also showed a wide spectrumof nuclear and chromosomal instabilities ranging from micronuclei nuclear blebbing chromosomal losses and gains that further implicate Lamin B2 in enhancing cancer associatednewlin newline newline