scholarly journals A DNA Replication-Independent Function of the pre-Replication Complex during Cell Invasion in C. elegans

2021 ◽  
Author(s):  
Evelyn Lattmann ◽  
Ting Deng ◽  
Michael Walser ◽  
Patrizia Widmer ◽  
Charlotte Rexha-Lambert ◽  
...  
Keyword(s):  
Dna Replication ◽  
Cell Invasion ◽  
Pi3k Pathway ◽  
Replication Initiation ◽  
Proliferating Cells ◽  
Replication Complex ◽  
Dna Replication Initiation ◽  
C Elegans ◽  
Initiation Factors ◽  
Dna Replication Origins

Cell invasion is an initiating event during tumor cell metastasis and an essential process during development. A screen of  C. elegans  orthologs of genes over-expressed in invasive human melanoma cells has identified several components of the conserved DNA pre-replication complex (pre-RC) as positive regulators of anchor cell (AC) invasion. The pre-RC functions cell-autonomously in the G1-arrested AC to promote invasion, independently of its role in licensing DNA replication origins in proliferating cells. While the helicase activity of the pre-RC is necessary for AC invasion, the downstream acting DNA replication initiation factors are not required. The pre-RC promotes the invasive fate by regulating the expression of extracellular matrix genes and components of the PI3K signaling pathway. Increasing PI3K pathway activity partially suppressed the AC invasion defects caused by pre-RC depletion, suggesting that the PI3K pathway is one critical pre-RC target. We propose that the pre-RC acts in the non-proliferating AC as a transcriptional regulator that facilitates the switch to an invasive phenotype.

scholarly journals Identification of the critical replication targets of CDK reveals direct regulation of replication initiation factors by the embryo polarity machinery in C. elegans

PLoS Genetics ◽  
2020 ◽  
Vol 16 (12) ◽  
pp. e1008948
Author(s):  
Vincent Gaggioli ◽  
Manuela R. Kieninger ◽  
Anna Klucnika ◽  
Richard Butler ◽  
Philip Zegerman
Keyword(s):  
Direct Interaction ◽  
Early Embryo ◽  
S Phase ◽  
Replication Initiation ◽  
Dna Replication Initiation ◽  
C Elegans ◽  
Initiation Factors ◽  
Physiological Importance ◽  
Essential Function ◽  
Phase Length

During metazoan development, the cell cycle is remodelled to coordinate proliferation with differentiation. Developmental cues cause dramatic changes in the number and timing of replication initiation events, but the mechanisms and physiological importance of such changes are poorly understood. Cyclin-dependent kinases (CDKs) are important for regulating S-phase length in many metazoa, and here we show in the nematode Caenorhabditis elegans that an essential function of CDKs during early embryogenesis is to regulate the interactions between three replication initiation factors SLD-3, SLD-2 and MUS-101 (Dpb11/TopBP1). Mutations that bypass the requirement for CDKs to generate interactions between these factors is partly sufficient for viability in the absence of Cyclin E, demonstrating that this is a critical embryonic function of this Cyclin. Both SLD-2 and SLD-3 are asymmetrically localised in the early embryo and the levels of these proteins inversely correlate with S-phase length. We also show that SLD-2 asymmetry is determined by direct interaction with the polarity protein PKC-3. This study explains an essential function of CDKs for replication initiation in a metazoan and provides the first direct molecular mechanism through which polarization of the embryo is coordinated with DNA replication initiation factors.

scholarly journals Transcription drives DNA replication initiation and termination in human cells

2018 ◽  
Author(s):  
Yu-Hung Chen ◽  
Sarah Keegan ◽  
Malik Kahli ◽  
Peter Tonzi ◽  
David Fenyö ◽  
...  
Keyword(s):  
Dna Replication ◽  
Rna Polymerase Ii ◽  
Replication Fork ◽  
Human Cells ◽  
Replication Initiation ◽  
Origin Firing ◽  
Dna Replication Initiation ◽  
Origin Activation ◽  
Dna Replication Origins ◽  
The Impact

ABSTRACTThe locations of active DNA replication origins in the human genome, and the determinants of origin activation, remain controversial. Additionally, neither the predominant sites of replication termination nor the impact of transcription on replication-fork mobility have been defined. We demonstrate that replication initiation occurs preferentially in the immediate vicinity of the transcription start site of genes occupied by high levels of RNA polymerase II, ensuring co-directional replication of the most highly transcribed genes. Further, we demonstrate that dormant replication origin firing represents the global activation of pre-existing origins. We also show that DNA replication naturally terminates at the polyadenylation site of transcribed genes. During replication stress, termination is redistributed to gene bodies, generating a global reorientation of replication relative to transcription. Our analysis provides a unified model for the coupling of transcription with replication initiation and termination in human cells.

scholarly journals Multiplication and division: Archaic modes of DNA replication initiation

2004 ◽  
Vol 26 (3) ◽  
pp. 11-15
Author(s):  
Nicholas P. Robinson ◽  
Stephen D. Bell
Keyword(s):  
Cell Division ◽  
Dna Replication ◽  
Genetic Material ◽  
Replication Initiation ◽  
Eukaryotic Cells ◽  
Bacterial Cells ◽  
Proliferating Cells ◽  
Dna Replication Initiation ◽  
The Third ◽  
Single Origin

Proliferating cells must produce a complete and accurate copy of their genetic material by DNA replication prior to cell division, and in all organisms this duplication begins at discrete sites known as replication origins. In eukaryotic cells, DNA synthesis is initiated from a large number of these regions, whereas bacterial cells replicate less complex genomes from a single origin. It is only in recent years that the process of replication initiation has become elucidated in the third domain of life, the Archaea.

Efficiency and equity in origin licensing to ensure complete DNA replication

2021 ◽  
Author(s):  
Liu Mei ◽  
Jeanette Gowen Cook
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Dna Replication ◽  
Genome Stability ◽  
S Phase ◽  
Replication Initiation ◽  
G1 Phase ◽  
Dna Replication Initiation ◽  
Origin Licensing ◽  
Dna Replication Origins

The cell division cycle must be strictly regulated during both development and adult maintenance, and efficient and well-controlled DNA replication is a key event in the cell cycle. DNA replication origins are prepared in G1 phase of the cell cycle in a process known as origin licensing which is essential for DNA replication initiation in the subsequent S phase. Appropriate origin licensing includes: (1) Licensing enough origins at adequate origin licensing speed to complete licensing before G1 phase ends; (2) Licensing origins such that they are well-distributed on all chromosomes. Both aspects of licensing are critical for replication efficiency and accuracy. In this minireview, we will discuss recent advances in defining how origin licensing speed and distribution are critical to ensure DNA replication completion and genome stability.

scholarly journals A predictable conserved DNA base composition signature defines human core DNA replication origins

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Ildem Akerman ◽  
Bahar Kasaai ◽  
Alina Bazarova ◽  
Pau Biak Sang ◽  
Isabelle Peiffer ◽  
...  
Keyword(s):  
Dna Replication ◽  
Dna Sequence ◽  
Cell Types ◽  
Replication Initiation ◽  
Replication Origins ◽  
Dna Base Composition ◽  
Dna Replication Initiation ◽  
Sequence Elements ◽  
Dna Replication Origins ◽  
Genomic Regions

Abstract DNA replication initiates from multiple genomic locations called replication origins. In metazoa, DNA sequence elements involved in origin specification remain elusive. Here, we examine pluripotent, primary, differentiating, and immortalized human cells, and demonstrate that a class of origins, termed core origins, is shared by different cell types and host ~80% of all DNA replication initiation events in any cell population. We detect a shared G-rich DNA sequence signature that coincides with most core origins in both human and mouse genomes. Transcription and G-rich elements can independently associate with replication origin activity. Computational algorithms show that core origins can be predicted, based solely on DNA sequence patterns but not on consensus motifs. Our results demonstrate that, despite an attributed stochasticity, core origins are chosen from a limited pool of genomic regions. Immortalization through oncogenic gene expression, but not normal cellular differentiation, results in increased stochastic firing from heterochromatin and decreased origin density at TAD borders.

scholarly journals Architectures of archaeal GINS complexes, essential DNA replication initiation factors

BMC Biology ◽  
2011 ◽  
Vol 9 (1) ◽  
pp. 28 ◽  
Author(s):  
Takuji Oyama ◽  
Sonoko Ishino ◽  
Seiji Fujino ◽  
Hiromi Ogino ◽  
Tsuyoshi Shirai ◽  
...  
Keyword(s):  
Dna Replication ◽  
Replication Initiation ◽  
Dna Replication Initiation ◽  
Initiation Factors

scholarly journals Girdin: an essential component of pre-replicative complex in human cells

2019 ◽  
Author(s):  
Lihong Wu ◽  
Yu Hua ◽  
Feiran Chang ◽  
Daochun Kong
Keyword(s):  
Dna Replication ◽  
Essential Role ◽  
Human Cells ◽  
Replication Initiation ◽  
The Other ◽  
Initiation Factor ◽  
Replication Origins ◽  
Initiation Factors ◽  
Initiation Of Dna Replication ◽  
Dna Replication Origins

AbstractA central event in the initiation of DNA replication in eukaryotes is the assembly of pre-replicative complex (pre-RC) on specific chromatin sites known as DNA replication origins. The pre-RC assembly process differs between budding and fission yeasts. In fission yeast, Sap1 directly participates in pre-RC assembly, together with the four initiation factors: ORC, Cdc18/Cdc6, Cdt1, and MCM. In metazoans, the nature of DNA replication origins is not defined and the mechanism of pre-RC assembly remains incompletely known. In this study, Girdin was identified as an essential replication initiation factor in human cells. Similar to the activity of Sap1, human Girdin binds to DNA origins, interacts with ORC, and is required for pre-RC assembly due to its essential role in recruitment of Cdc6 to DNA origins. Thus, DNA origins in human or metazoans are defined as including two elements, one bound by ORC and the other bound by Girdin.

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