Mammalian chromosomes contain<i>cis</i>‐acting elements that control replication timing, mitotic condensation, and stability of entire chromosomes

Thayer, Mathew J.

doi:10.1002/bies.201200035

Cited by 26 publications

(22 citation statements)

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“…Thus, we propose a model for the instability of individual chromosomes that includes: 1) delayed replication timing of individual chromosomes caused by genetic disruption of cis -acting loci (e.g. ASAR6 or Xist ); 2) delayed recruitment of Aurora B kinase resulting in delayed mitotic chromosome condensation; 3) delayed mitotic spindle attachment leading to chromosome missegregation, bridged chromosomes, and the formation of micronuclei; 4) the onset of mitotic chromosome condensation prior to the completion of DNA synthesis leading to stalled replication forks; and 5) multiple rearrangements generated at the stalled replication forks via replicative mechanisms (Figure S7; also see [1]). …”

Section: Discussionmentioning

confidence: 99%

“…Morphological differences between mitotic chromosomes residing within the same cell were first described in mammalian cells over forty years ago (reviewed in [1]). In addition, numerous reports have described an abnormal chromosomal phenotype affecting single or a few chromosomes in mitotic preparations from tumor-derived and other established cell lines.…”

Section: Introductionmentioning

confidence: 99%

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Asynchronous Replication, Mono-Allelic Expression, and Long Range Cis-Effects of ASAR6

et al. 2013

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Asynchronous Replication, Mono-Allelic Expression, and Long Range Cis-Effects of ASAR6

et al. 2013

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“…Heterochromatin formation and replication delay can be regulated by distinct DNA sequences at distal loci, possibly operated via non-coding RNAs such as XIST for the X chromosome 115; 116 and ASAR6 for the autosomal chromosome 6 in cancer cells. 117; 118 These long non-coding RNA are are implicated in the control of mono-allelic expression, but may more broadly be involved in chromosomal maintenance throughout the cell cycle. 118 Such loci can mediate long-range chromatin effects via RNAi, analogous to similar mechanisms shown for heterochromatin spread in S. pombe.…”

Section: Replicators: Dna Sequences As Chromatin Organizers?mentioning

confidence: 99%

Chromatin Structure and Replication Origins: Determinants of Chromosome Replication and Nuclear Organization

Smith

Aladjem

2014

Journal of Molecular Biology

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The DNA replication program is, in part, determined by the epigenetic landscape that governs local chromosome architecture and directs chromosome duplication. Replication must coordinate with other biochemical processes occurring concomitantly on chromatin, such as transcription and remodeling, to insure accurate duplication of both genetic and epigenetic features and to preserve genomic stability. The importance of genome architecture and chromatin looping in coordinating cellular processes on chromatin is illustrated by two recent sets of discoveries. First, chromatin-associated proteins that are not part of the core replication machinery were shown to affect the timing of DNA replication. These chromatin-associated proteins could be working in concert, or perhaps in competition, with the transcriptional machinery and with chromatin modifiers to determine the spatial and temporal organization of replication initiation events. Second, epigenetic interactions are mediated by DNA sequences that determine chromosomal replication. In this review we summarize recent findings and current models linking spatial and temporal regulation of the replication program with epigenetic signaling. We discuss these issues in the context of the genome’s three-dimensional structure with an emphasis on events occurring during the initiation of DNA replication.

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“…Given the similarities in structure and function of the two loci characterized to date, Xist and ASAR6, it was proposed that all mammalian chromosomes contain functional chromosome “inactivation/stability centers” that act to maintain proper replication timing and structural stability of individual chromosomes [127]. Under this scenario every mammalian chromosome contains four cis-acting elements, origins of replication, centromeres, telomeres, and ‘inactivation/stability centers’, all functioning to ensure proper replication, segregation and stability of individual chromosomes [131]. …”

Section: Dna Replication Timing and The Evolution Of The Cancer Gementioning

confidence: 99%

DNA replication timing, genome stability and cancer

Donley

Thayer

2013

Seminars in Cancer Biology

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Normal cellular division requires that the genome be faithfully replicated to ensure that unaltered genomic information is passed from one generation to the next. DNA replication initiates from thousands of origins scattered throughout the genome every cell cycle; however, not all origins initiate replication at the same time. A vast amount of work over the years indicates that different origins along each eukaryotic chromosome are activated in early, middle or late S phase. This temporal control of DNA replication is referred to as the replication-timing program. The replication-timing program represents a very stable epigenetic feature of chromosomes. Recent evidence has indicated that the replication-timing program can influence the spatial distribution of mutagenic events such that certain regions of the genome experience increased spontaneous mutagenesis compared to surrounding regions. This influence has helped shape the genomes of humans and other multicellular organisms and can affect the distribution of mutations in somatic cells. It is also becoming clear that the replication-timing program is deregulated in many disease states, including cancer. Aberrant DNA replication timing is associated with changes in gene expression, changes in epigenetic modifications and an increased frequency of structural rearrangements. Furthermore, certain replication timing changes can directly lead to overt genomic instability and may explain unique mutational signatures that are present in cells that have undergone the recently described processes of “chromothripsis” and “kataegis”. In this review, we will discuss how the normal replication timing program, as well as how alterations to this program, can contribute to the evolution of the genomic landscape in normal and cancerous cells.

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Mammalian chromosomes containcis‐acting elements that control replication timing, mitotic condensation, and stability of entire chromosomes

Cited by 26 publications

References 86 publications

Asynchronous Replication, Mono-Allelic Expression, and Long Range Cis-Effects of ASAR6

Asynchronous Replication, Mono-Allelic Expression, and Long Range Cis-Effects of ASAR6

Chromatin Structure and Replication Origins: Determinants of Chromosome Replication and Nuclear Organization

DNA replication timing, genome stability and cancer

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