Abstract
Mammalian chromosomes initiate DNA replication at multiple sites along their length during each S phase following a temporal replication program. The majority of genes on homologous chromosomes replicate synchronously. However, mono-allelically expressed genes such as imprinted genes, allelically excluded genes, and genes on female X chromosomes replicate asynchronously. We have identified a cis-acting locus on human chromosome 6 that controls this replication-timing program. This locus encodes a large intergenic non-coding RNA gene named Asynchronous replication and Autosomal RNA on chromosome 6, or ASAR6. Disruption of ASAR6 results in delayed replication, delayed mitotic chromosome condensation, and activation of the previously silent alleles of mono-allelic genes on chromosome 6. The ASAR6 gene resides within an ∼1.2 megabase domain of asynchronously replicating DNA that is coordinated with other random asynchronously replicating loci along chromosome 6. In contrast to other nearby mono-allelic genes, ASAR6 RNA is expressed from the later-replicating allele. ASAR6 RNA is synthesized by RNA Polymerase II, is not polyadenlyated, is restricted to the nucleus, and is subject to random mono-allelic expression. Disruption of ASAR6 leads to the formation of bridged chromosomes, micronuclei, and structural instability of chromosome 6. Finally, ectopic integration of cloned genomic DNA containing ASAR6 causes delayed replication of entire mouse chromosomes.
Highlights
Morphological differences between mitotic chromosomes residing within the same cell were first described in mammalian cells over forty years ago
Chromosomes with delay in replication timing (DRT) display a delay in mitotic chromosome condensation (DMC), which is characterized by an under-condensed appearance during mitosis, delayed recruitment of Aurora B kinase, and a delay in the mitotic phosphorylation of serine 10 of histone H3 [5,6]
We have identified a locus on human chromosome 6 that shares many characteristics with XIST
Summary
Morphological differences between mitotic chromosomes residing within the same cell were first described in mammalian cells over forty years ago (reviewed in [1]). The individual under-condensed chromosomes synthesized DNA after the normally condensed chromosomes had finished replication, indicating that the undercondensed chromosomes were extremely late replicating, with DNA synthesis extending into the G2 phase. These observations have been extended to include chromosomes present in numerous tumor-derived and permanent cell lines from several different mammalian species [3,4,5]. The DRT/DMC phenotype was detected on ,5% of inter-chromosomal translocations induced by exposure to ionizing radiation (IR) [7] Taken together, these observations indicate that DRT/DMC occurs on certain rearranged chromosomes and is a common phenotype in cancer cells and in cells exposed to IR
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