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The DNA Replication Fork01:02

The DNA Replication Fork

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An organism’s genome needs to be duplicated in an efficient and error-free manner for its growth and survival. The replication fork is a Y-shaped active region where two strands of DNA are separated and replicated continuously. The coupling of DNA unzipping and complementary strand synthesis is a characteristic feature of a replication fork.   Organisms with small circular DNA, such as E. coli, often have a single origin of replication; therefore, they have only two replication...
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In eukaryotic cells, DNA replication is highly conserved and tightly regulated. Multiple linear chromosomes must be duplicated with high fidelity before cell division, so there are many proteins that fulfill specialized roles in the replication process. Replication occurs in three phases: initiation, elongation, and termination, and ends with two complete sets of chromosomes in the nucleus.
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DNA Damage can Stall the Cell Cycle02:37

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In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
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DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
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During replication, the complementary strands in double-stranded DNA are synthesized at different rates. Replication first begins on the leading strand. Replication starts later, occurs more slowly, and proceeds discontinuously on the lagging strand.
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The cell cycle is a series of events leading to DNA duplication followed by the division of cell content to form two daughter cells. The cell cycle progresses in four stages—the cell increases in size (gap 1 or G1-phase), duplicates its DNA (synthesis or S-phase), prepares to divide (gap 2 or G2-phase), and divides (mitosis or M-phase).
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In vivo DNA replication dynamics unveil aging-dependent replication stress.

Giacomo G Rossetti1, Noëlle Dommann2, Angeliki Karamichali1

  • 1Department of Molecular and Cellular Biology, University of Geneva, Geneva 1205, Switzerland.

Cell
|September 18, 2024
PubMed
Summary

Aging impairs DNA replication initiation in mouse livers, causing replication stress. ATR inhibition restored origin firing but increased inflammation, highlighting ATR's role in mitigating age-related stress.

Keywords:
ATRDNA replicationDNA replication stressagingcryptic DNA damageliver regenerationorigin of replicationpartial hepatectomy

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Area of Science:

  • Molecular Biology
  • Genetics
  • Cellular Biology

Background:

  • Genome duplication is crucial for cell proliferation and is influenced by aging.
  • DNA replication initiation sites are generally conserved across species, but their efficiency can be affected by age.

Purpose of the Study:

  • To investigate the impact of aging on DNA replication initiation dynamics in regenerating mouse livers.
  • To explore the role of ATR (Ataxia Telangiectasia and Rad3-related) checkpoint kinase in age-related replication stress.

Main Methods:

  • Partial hepatectomy was performed on young and old mice to induce liver regeneration.
  • DNA replication initiation sites were monitored in both age groups.
  • ATR checkpoint kinase inhibitors were administered to old mice to assess their effect on origin firing and cellular responses.

Main Results:

  • Young mice exhibited well-defined DNA replication origins, conserved in human cells.
  • Old mice showed inefficient origin firing at conserved sites, triggering a replication stress response.
  • ATR inhibition restored origin firing efficiency in old mice but induced inflammation and did not significantly increase cell cycle entry.

Conclusions:

  • Aging leads to replication stress during liver regeneration.
  • ATR plays a critical role in managing age-dependent replication stress and associated inflammation.
  • Targeting ATR may offer therapeutic strategies for age-related cellular dysfunction.