Eukaryotic DNA Replication in a Chromatin Context

Molecular and Computational Biology Section University of Southern California Los Angeles, California 90089, USA.
Current Topics in Developmental Biology (Impact Factor: 4.68). 02/2006; 76:129-84. DOI: 10.1016/S0070-2153(06)76005-7
Source: PubMed


There has been remarkable progress in the last 20 years in defining the molecular mechanisms that regulate initiation of DNA synthesis in eukaryotic cells. Replication origins in the DNA nucleate the ordered assembly of protein factors to form a prereplication complex (preRC) that is poised for DNA synthesis. Transition of the preRC to an active initiation complex is regulated by cyclin-dependent kinases and other signaling molecules, which promote further protein assembly and activate the mini chromosome maintenance helicase. We will review these mechanisms and describe the state of knowledge about the proteins involved. However, we will also consider an additional layer of complexity. The DNA in the cell is packaged with histone proteins into chromatin. Chromatin structure provides an additional layer of heritable information with associated epigenetic modifications. Thus, we will begin by describing chromatin structure, and how the cell generally controls access to the DNA. Access to the DNA requires active chromatin remodeling, specific histone modifications, and regulated histone deposition. Studies in transcription have revealed a variety of mechanisms that regulate DNA access, and some of these are likely to be shared with DNA replication. We will briefly describe heterochromatin as a model for an epigenetically inherited chromatin state. Next, we will describe the mechanisms of replication initiation and how these are affected by constraints of chromatin. Finally, chromatin must be reassembled with appropriate modifications following passage of the replication fork, and our third major topic will be the reassembly of chromatin and its associated epigenetic marks. Thus, in this chapter, we seek to bring together the studies of replication initiation and the studies of chromatin into a single holistic narrative.

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    • "Hence, they do not necessarily alter the frequency of switching. Mutations in other regulators produce higher levels of the expression of otherwise silenced reporters [89,90], but it is hard to tell if modest loss of repression or frequent epigenetic conversions have yielded these results. "
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    Epigenetics & Chromatin 11/2013; 6(1):40. DOI:10.1186/1756-8935-6-40 · 5.33 Impact Factor
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    • "Such phenomena should not be linked to the switching mechanism. On the other hand, many studies have shown increased levels of expression of otherwise silenced reporters [reviewed in (3,12)]. These observations have often been attributed to ‘poor maintenance’ of gene silencing, meaning an elevated rate of S→A switches, or to incomplete repression of the gene in the PEV locus. "
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    Nucleic Acids Research 07/2013; 41(18). DOI:10.1093/nar/gkt623 · 9.11 Impact Factor
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    • "We find coevolution with members of the minichromosome maintenance complex (MCMC), proteins involved in replication as a part of the pre-replication complex. MCMC proteins have also been implicated in diverse chromosome transactions including genome stability, transcription, and chromatin modification (Tabancay and Forsburg 2006). We find some of these MCMC proteins to be coevolving with TCP1 and other members of the CCT complex. "
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    ABSTRACT: Coevolution maintains interactions between phenotypic traits through the process of reciprocal natural selection. Detecting molecular coevolution can expose functional interactions between molecules in the cell, generating insights into biological processes, pathways, and the networks of interactions important for cellular function. Prediction of interaction partners from different protein families exploits the property that interacting proteins can follow similar patterns and relative rates of evolution. Current methods for detecting coevolution based on the similarity of phylogenetic trees or evolutionary distance matrices have, however, been limited by requiring coevolution over the entire evolutionary history considered and are inaccurate in the presence of paralogous copies. We present a novel method for determining coevolving protein partners by finding the largest common submatrix in a given pair of distance matrices, with the size of the largest common submatrix measuring the strength of coevolution. This approach permits us to consider matrices of different size and scale, to find lineage-specific coevolution, and to predict multiple interaction partners. We used MatrixMatchMaker to predict protein-protein interactions in the human genome. We show that proteins that are known to interact physically are more strongly coevolving than proteins that simply belong to the same biochemical pathway. The human coevolution network is highly connected, suggesting many more protein-protein interactions than are currently known from high-throughput and other experimental evidence. These most strongly coevolving proteins suggest interactions that have been maintained over long periods of evolutionary time, and that are thus likely to be of fundamental importance to cellular function.
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