Dataset Information

Heterochromatin on the inactive X chromosome delays replication timing without affecting origin usage.

ABSTRACT: DNA replication origins (ORIs) map close to promoter regions in many organisms, including mammals. However, the relationship between initiation of replication and transcription is not well understood. To address this issue, we have analyzed replication timing and activity of several CpG island-associated ORIs on the transcriptionally active and silent X chromosomes. We find equivalent ORI usage and efficiency of both alleles at sites that are replicated late on the inactive X chromosome. Thus, in contrast to its repressive effect on transcription, heterochromatin does not influence ORI activity. These findings suggest that the relationship between sites of transcription and replication initiation at CpG island regions is restricted to early development, and that subsequent gene silencing and heterochromatin formation influence only the timing of ORI activation.

SUBMITTER: Gomez M

PROVIDER: S-EPMC406443 | biostudies-literature | 2004 May

REPOSITORIES: biostudies-literature

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Heterochromatin on the inactive X chromosome delays replication timing without affecting origin usage.

Gómez María M Brockdorff Neil N

Proceedings of the National Academy of Sciences of the United States of America 20040422 18

DNA replication origins (ORIs) map close to promoter regions in many organisms, including mammals. However, the relationship between initiation of replication and transcription is not well understood. To address this issue, we have analyzed replication timing and activity of several CpG island-associated ORIs on the transcriptionally active and silent X chromosomes. We find equivalent ORI usage and efficiency of both alleles at sites that are replicated late on the inactive X chromosome. Thus, i ...[more]

PMID: 15105447

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Project description:Chromosome replication is regulated in all organisms at the assembly stage of the replication machinery at specific origins. In Escherichia coli, the DnaA initiator protein regulates the assembly of replication forks at oriC. This regulation can be undermined by defects in nucleic acid metabolism. In cells lacking RNase HI, replication initiates independently of DnaA and oriC, presumably at persisting R-loops. A similar mechanism was assumed for origin-independent synthesis in cells lacking RecG. However, recently we suggested that this synthesis initiates at intermediates resulting from replication fork fusions. Here we present data suggesting that in cells lacking RecG or RNase HI, origin-independent synthesis arises by different mechanisms, indicative of these two proteins having different roles in vivo. Our data support the idea that RNase HI processes R-loops, while RecG is required to process replication fork fusion intermediates. However, regardless of how origin-independent synthesis is initiated, a fraction of forks will proceed in an orientation opposite to normal. We show that the resulting head-on encounters with transcription threaten cell viability, especially if taking place in highly transcribed areas. Thus, despite their different functions, RecG and RNase HI are both important factors for maintaining replication control and orientation. Their absence causes severe replication problems, highlighting the advantages of the normal chromosome arrangement, which exploits a single origin to control the number of forks and their orientation relative to transcription, and a defined termination area to contain fork fusions. Any changes to this arrangement endanger cell cycle control, chromosome dynamics, and, ultimately, cell viability.Cell division requires unwinding of millions of DNA base pairs to generate the template for RNA transcripts as well as chromosome replication. As both processes use the same template, frequent clashes are unavoidable. To minimize the impact of these clashes, transcription and replication in bacteria follow the same directionality, thereby avoiding head-on collisions. This codirectionality is maintained by a strict regulation of where replication is started. We have used Escherichia coli as a model to investigate cells in which the defined location of replication initiation is compromised. In cells lacking either RNase HI or RecG, replication initiates away from the defined replication origin, and we discuss the different mechanisms by which this synthesis arises. In addition, the resulting forks proceed in a direction opposite to normal, thereby inducing head-on collisions between transcription and replication, and we show that the resulting consequences are severe enough to threaten the viability of cells.

Dataset Information

Heterochromatin on the inactive X chromosome delays replication timing without affecting origin usage.

Publications

Heterochromatin on the inactive X chromosome delays replication timing without affecting origin usage.

Similar Datasets

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