dna replication origins
Recently Published Documents


TOTAL DOCUMENTS

193
(FIVE YEARS 34)

H-INDEX

36
(FIVE YEARS 5)

2022 ◽  
Author(s):  
Yaqun Liu ◽  
Xia Wu ◽  
Yves D'aubenton-Carafa ◽  
Claude Thermes ◽  
Chun-Long Chen

Motivation: During each cell division, tens of thousands of DNA replication origins are coordinately activated to ensure the complete duplication of the entire human genome. However, the progression of replication forks can be challenged by numerous factors. One such factor is transcription-replication conflicts (TRC), which can either be co-directional or head-on with the latter being revealed as more dangerous for genome integrity. Results: In order to study the direction of replication fork movement and TRC, we developed a bioinformatics tool, called OKseqHMM, to directly measure the genome-wide replication fork directionality (RFD) as well as replication initiation and termination from data obtained by Okazaki fragment sequencing (OK-Seq) and related techniques. Availability and Implementation: We have gathered and analyzed OK-seq data from a large number of organisms including yeast, mouse and human, to generate high-quality RFD profiles and determine initiation zones and termination zones by using Hidden Markov Model (HMM) algorithm (all tools and data are available at https://github.com/CL-CHEN-Lab/OK-Seq). In addition, we have extended our analysis to data obtained by related techniques, such as eSPAN and TrAEL-seq, which also contain RFD information. Our works, therefore, provide an important tool and resource for the community to further study TRC and genome instability, in a wide range of cell line models and growth conditions, which is of prime importance for human health.


Life ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 108
Author(s):  
Marco Saponaro

Transcription and replication are the two most essential processes that a cell does with its DNA: they allow cells to express the genomic content that is required for their functions and to create a perfect copy of this genomic information to pass on to the daughter cells. Nevertheless, these two processes are in a constant ambivalent relationship. When transcription and replication occupy the same regions, there is the possibility of conflicts between transcription and replication as transcription can impair DNA replication progression leading to increased DNA damage. Nevertheless, DNA replication origins are preferentially located in open chromatin next to actively transcribed regions, meaning that the possibility of conflicts is potentially an accepted incident for cells. Data in the literature point both towards the existence or not of coordination between these two processes to avoid the danger of collisions. Several reviews have been published on transcription–replication conflicts, but we focus here on the most recent findings that relate to how these two processes are coordinated in eukaryotes, considering advantages and disadvantages from coordination, how likely conflicts are at any given time, and which are their potential hotspots in the genome.


Author(s):  
Liu Mei ◽  
Jeanette Gowen Cook

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.


2021 ◽  
Author(s):  
Liu Mei ◽  
Katarzyna M. Kedziora ◽  
Eun-ah Song ◽  
Jeremy E Purvis ◽  
Jeanette Gowen Cook

MCM complexes are loaded onto chromosomes to license DNA replication origins in G1 phase of the cell cycle, but it is not yet known how mammalian MCM complexes are adequately distributed to both euchromatin and heterochromatin. To address this question, we combined time-lapse live-cell imaging with fixed cell immunofluorescence imaging of single human cells to quantify the relative rates of MCM loading in heterochromatin and euchromatin at different times within G1. We report here that MCM loading in euchromatin is faster than in heterochromatin in very early G1, but surprisingly, heterochromatin loading accelerates faster than euchromatin in middle and late G1. These different loading dynamics require ORCA-dependent differences in ORC distribution during G1. A consequence of heterochromatin origin licensing dynamics is that cells experiencing a truncated G1 phase from premature Cyclin E expression enter S phase with underlicensed heterochromatin, and DNA damage accumulates preferentially in heterochromatin in the subsequent S/G2 phase. Thus G1 length is critical for sufficient MCM loading, particularly in heterochromatin, to ensure complete genome duplication and to maintain genome stability.


2021 ◽  
Author(s):  
Evelyn Lattmann ◽  
Ting Deng ◽  
Michael Walser ◽  
Patrizia Widmer ◽  
Charlotte Rexha-Lambert ◽  
...  

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.


2021 ◽  
Author(s):  
Yoko Hayashi-Takanaka ◽  
Yuichiro Hayashi ◽  
Yasuhiro Hirano ◽  
Atsuko Miyawaki-Kuwakado ◽  
Yasuyuki Ohkawa ◽  
...  

Replication of genomic DNA is a key step in initiating cell proliferation. Loading hexameric complexes of minichromosome maintenance (MCM) helicase on DNA replication origins during the G1 phase is essential in initiating DNA replication. Here, we show that stepwise loading of two hexamer complexes of MCM occurs during G1 progression in human cells. This transition from the single-to-double hexamer was associated with levels of methylation at lysine 20 of histone H4 (H4K20). A single hexamer of MCM complexes was loaded at the replication origins with the presence of H4K20 monomethylation (H4K20me1) in the early G1 phase, then another single hexamer was recruited to form a double hexamer later in G1 as H4K20me1 was converted to di-/tri-methylation (H4K20me2/me3). Under non-proliferating conditions, cells stay halted at the single-hexamer state in the presence of H4K20me1. We propose that the single-hexamer state on chromatin is a limiting step in making the proliferation-quiescence decision.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Humberto Sánchez ◽  
Kaley McCluskey ◽  
Theo van Laar ◽  
Edo van Veen ◽  
Filip M. Asscher ◽  
...  

AbstractDNA replication in eukaryotes initiates at many origins distributed across each chromosome. Origins are bound by the origin recognition complex (ORC), which, with Cdc6 and Cdt1, recruits and loads the Mcm2-7 (MCM) helicase as an inactive double hexamer during G1 phase. The replisome assembles at the activated helicase in S phase. Although the outline of replisome assembly is understood, little is known about the dynamics of individual proteins on DNA and how these contribute to proper complex formation. Here we show, using single-molecule optical trapping and confocal microscopy, that yeast ORC is a mobile protein that diffuses rapidly along DNA. Origin recognition halts this search process. Recruitment of MCM molecules in an ORC- and Cdc6-dependent fashion results in slow-moving ORC-MCM intermediates and MCMs that rapidly scan the DNA. Following ATP hydrolysis, salt-stable loading of MCM single and double hexamers was seen, both of which exhibit salt-dependent mobility. Our results demonstrate that effective helicase loading relies on an interplay between protein diffusion and origin recognition, and suggest that MCM is stably loaded onto DNA in multiple forms.


2021 ◽  
Author(s):  
Timothy Hoggard ◽  
Allison J. Hollatz ◽  
Rachel Cherney ◽  
Catherine A. Fox

AbstractThe pioneer event in eukaryotic DNA replication is binding of chromosomal DNA by the origin recognition complex (ORC), which directs the formation of origins, the specific chromosomal regions where DNA will be unwound for the initiation of DNA synthesis. In all eukaryotes, incompletely understood features of chromatin promote ORC-DNA binding. Here, we uncover a role for the Fkh1 (forkhead homolog) protein, and, in particular, its forkhead associated (FHA) domain in promoting ORC-origin binding and origin activity at a subset of origins in Saccharomyces cerevisiae. The majority of the FHA-dependent origins within the experimental subset examined contain a distinct Fkh1 binding site located 5’ of and proximal to their ORC sites (5’-FKH-T site). Epistasis experiments using selected FHA-dependent origins provided evidence that the FHA domain promoted origin activity through Fkh1 binding directly to this 5’ FKH-T site. Nucleotide substitutions within two of these origins that enhanced the affinity of their ORC sites for ORC bypassed these origins’ requirement for their 5’ FKH-T sites and for the FHA domain. Significantly, direct assessment of ORC-origin binding by ChIPSeq provided evidence that this mechanism affected ~25% of yeast origins. Thus, this study reveals a new mechanism to enhance ORC-origin binding in budding yeast that requires the FHA domain of the conserved cell-cycle transcription factor Fkh1.


2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Ildem Akerman ◽  
Bahar Kasaai ◽  
Alina Bazarova ◽  
Pau Biak Sang ◽  
Isabelle Peiffer ◽  
...  

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.


2020 ◽  
Vol 74 (1) ◽  
pp. 65-80 ◽  
Author(s):  
Mark D. Greci ◽  
Stephen D. Bell

It is now well recognized that the information processing machineries of archaea are far more closely related to those of eukaryotes than to those of their prokaryotic cousins, the bacteria. Extensive studies have been performed on the structure and function of the archaeal DNA replication origins, the proteins that define them, and the macromolecular assemblies that drive DNA unwinding and nascent strand synthesis. The results from various archaeal organisms across the archaeal domain of life show surprising levels of diversity at many levels—ranging from cell cycle organization to chromosome ploidy to replication mode and nature of the replicative polymerases. In the following, we describe recent advances in the field, highlighting conserved features and lineage-specific innovations.


Sign in / Sign up

Export Citation Format

Share Document