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Description Table of Contents Product Details Click on the cover image above to read some pages of this book! Chapter 1. PMID: Homeostatic control of polo-like kinase-1 engenders non-genetic heterogeneity in G2 checkpoint fidelity and timing. Nature Commun.
Dual effect of heat shock on DNA replication and genome integrity
Human inositol polyphosphate kinase regulates transcript-selective nuclear mRNA export to preserve genome integrity. Wickramasinghe, V. Chavali, S. Molecular Cell. Cell Cycle. Modifying chromatin architecture during the response to DNA breakage. Venkitaraman AR. Crit Rev Biochem Mol Biol.
Cell-cycle coordination between DNA replication and recombination revealed by a vertebrate N-end rule degron-Rad Nat Struct Mol Biol. The duplicated DNA is then segregated into two "daughter" cells that inherit the same genetic information. This process is called chromosome segregation.
DNA Structure, Replication, and Technology
Because DNA is a depository of genetic information, DNA replication and segregation must be achieved with extreme fidelity. Healthy cells can perform DNA replication with almost absolute accuracy most of the time.
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Considering that a eukaryotic cell contains millions or billions of DNA base pairs, this is a remarkable accomplishment. It seems that DNA replication is far more difficult than one might think. So, what could interfere with DNA replication? For example, UV light creates cyclobutane dimers between two thymidine residues in DNA that stall the progression of the replication machinery. Drugs or toxins are also major causes of DNA damage. It is also important to note that reactive oxygen species generated by normal cellular metabolism can also cause DNA damage and block DNA replication.
Replication blockage is not only caused by DNA damage Figure 1. These include various DNA binding proteins such as the transcription machinery. Another physical barrier could be the DNA structure itself. Repeated DNA sequences form complex 3-dimensional structures such as telomeres, centromeres and ribosomal DNA and may be difficult to replicate.
Highly ordered chromatin structures also cause replication problems, as they are very compact and wrap around histone proteins, and in turn result in highly ordered structures. All of these can cause replication fork stalling Figure 1. One way to envision the replication fork is to think about bicycling. It is quite easy to keep your balance when you are moving forward.
But once you stop, it is difficult to keep upright without stepping on the ground. If you don't step on the ground, you may fall down. How does a cell circumvent these problems? How does a cell achieve accurate replication of genomes under such daunting conditions? In , Leland Hartwell and Ted Weinert proposed that a cell possesses dedicated quality control systems that monitor problems on DNA templates.
The checkpoints detect various issues found on DNA.
- DNA-protein interactions;
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- DNA Structure, Replication, and Technology.
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Once checkpoint proteins identify these issues, the cell activates signal transduction pathways in order to arrest the progression of the cell cycle and allow adequate time to fix the problems on DNA. What does the DNA replication checkpoint really monitor? This checkpoint monitors the most important site when the cell is replicating DNA.
When the fork stalls due to an obstacle on the DNA Figure 1 , the cell activates the replication checkpoint to send a signal to arrest the progression of the cell cycle. When the fork stalls or breaks, the cell sequentially activates signal transduction proteins to ensure that offspring inherit accurate copies of parental DNA. These activities prevent the cell from moving into the later phases of the cell cycle, ensuring that the cells do not pass on incomplete or altered genetic information to the daughter cells. What else, then, does the replication checkpoint do? Therefore, it is also important to prevent DNA damage at the replication fork by maintaining assembly of the replisome the replication machinery components and DNA structures in replication competent states when forks stall.
Recent studies identified a group of proteins that are required to stabilize replication forks Figure 3. These fork protectors may include proteins related to Timeless, Tipin, and Claspin Abraham ; Katou et al. Several concurrent processes are occurring during DNA replication at the replication fork, so fork protectors may have other functions. For example, sister chromatid cohesion is an essential process required for accurate segregation of chromosomes. After DNA replication, the cohesion mechanism holds duplicated sister chromatids together until they are ready for separation at mitosis.
Importantly, there are cohesins — proteins that are required for cohesion — that are loaded onto the chromosome before DNA replication.
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Although exactly how it happens is controversial, scientists think cohesin proteins form ring-like structures and wrap around the chromosome. Indeed, downregulation of fork protectors results in cohesion defects Leman et al. Another example of cellular processes at the replication fork is chromatin regulation. Chromatin contains histone proteins that are required for the assembly of nucleosomes, the fundamental unit of chromatin. Chromatin structure has a large impact on DNA replication and repair programs. During DNA replication, cells need to disassemble nucleosomes ahead of the replication fork and reassemble them behind the fork Figure 5.
At the same time, in S-phase, cells need to synthesize new histone proteins which will also be deposited to newly replicated DNA. Such orchestration of DNA replication processes in the context of chromatin — so called DNA replication-coupled nucleosome assembly — is extremely important for accurate transmission of genetic and epigenetic information Annunziato ; Groth et al. Therefore, it is likely that replication fork proteins are involved in regulation of chromatin structures Figure 4. When a replication block, such as one resulting from hydroxyurea-mediated depletion of nucleotide pools, is encountered, fork progression stalls.
The replisome is stabilized by factors that associate with the RF, allowing stalled forks to restart replication once the block has been removed. If RFs are not stabilized, the fork collapses, leading to ssDNA gaps and double-strand breaks, which activate the intra-S phase checkpoint.
Alternative, error-prone pathways are used to restart replication and can result in genome instability. INO80 could act on nucleosomes either in front of or behind the fork to preserve RF integrity. INO80 meets a fork in the road. All rights reserved. When the fork stalls, the replication checkpoint steps in and identifies the problems with the DNA. This checkpoint activates a signal transduction cascade to arrest the cell cycle and coordinate with the DNA repair programs.
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- Further readings.