Developmental Regulation of the Origin Recognition Complex

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The Origin Recognition Complex is required for site-specific replication initiation in eukaryotic chromosomes. Null mutations are lethal in yeast and metazoa, and hypomorphs induce genome instability, a hallmark of cancer. We exploited the unique biology of Tetrahymena to explore ORC's role in conventional and alternative replication programs. Modest experimental down-regulation of ORC1 induces genome instability in vegetative growing Tetrahymena, and diminishes the capacity to support developmentally regulated endoreplication and gene amplification, consistent with essential roles in all of these processes. ORC mutants fail to activate the ATR checkpoint response, and are compromised in their ability to elongate existing replication forks. Remarkably, ORC and MCM levels fluctuate in unexpected ways during wild type development. Most notably, programmed changes in ORC abundance do not reflect the impending DNA replication load. Relative to the vegetative cell cycle, ORC and MCM levels increase dramatically and are highest early in development, when the replication load is lowest. Conversely, ORC levels are lowest during genome-wide macronuclear endoreplication, when the replication load increases. Endocycling cells generate unconventional replication intermediates that distinguish them from vegetative ORC1 knockdown mutants. The collective data suggest that the dependence on ORC may be relaxed during late stages of macronuclear development.

Vyšlo v časopise: Developmental Regulation of the Origin Recognition Complex. PLoS Genet 11(1): e32767. doi:10.1371/journal.pgen.1004875
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004875

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