Early disruption of centromeric chromatin organisation in centromere protein-A (Cenpa) null mice

EV Howman, KJ Fowler, AJ Newson, S Redward, AC MacDonald, P Kalitsis, KHA Choo

Research output: Contribution to journalArticle (Academic Journal)

307 Citations (Scopus)

Abstract

Centromere protein A (Cenpa for mouse, CENP-A for other species) is a histone H3-like protein that is thought to be involved in the nucleosomal packaging of centromeric DNA. Using gene targeting, we have disrupted the mouse Cenpa gene and demonstrated that the gene is essential. Heterozygous mice are healthy and fertile whereas null mutants fail to survive beyond 6.5 days postconception. Affected embryos show severe mitotic problems, including micronuclei and macronuclei formation, nuclear bridging and blebbing, and chromatin fragmentation and hypercondensation. Immunofluorescence analysis of interphase cells at day 5.5 reveals complete Cenpa depletion, diffuse Cenpb foci, absence of discrete Cenpc signal on centromeres, and dispersion of Cenpb and Cenpc throughout the nucleus. These results suggest that Cenpa is essential for kinetochore targeting of Cenpc and plays an early role in organizing centromeric chromatin at interphase. The evidence is consistent with the proposal of a critical epigenetic function for CENP-A in marking a chromosomal region for centromere formation.
Translated title of the contributionEarly disruption of centromeric chromatin organisation in centromere protein-A (Cenpa) null mice
Original languageEnglish
Pages (from-to)1148 - 1153
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97(3)
DOIs
Publication statusPublished - 2000

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