Related Experiment Video
Updated: Jun 27, 2025
08:34
Utilizing Murine Inducible Telomerase Alleles in the Studies of Tissue Degeneration/Regeneration and Cancer
Published on: April 13, 2015
10.3K
Deregulated DNA ADP-ribosylation impairs telomere replication
Anne R Wondisford1, Junyeop Lee2, Robert Lu3
1Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
Nature Structural & Molecular Biology
|May 7, 2024
Summary
DNA ADP-ribosylation (DNA-ADPr) occurs at telomeres, regulated by PARP1 and TARG1. Dysregulation of this process compromises telomere replication and integrity, impacting genome stability.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- ADP-ribosylation is a post-translational modification with roles in genome stability, epigenetics, and immunity.
- The specific role and regulation of DNA ADP-ribosylation (DNA-ADPr) in maintaining genome stability remain largely unknown.
Purpose of the Study:
- To investigate whether DNA-ADPr contributes to genome stability.
- To elucidate the mechanisms regulating DNA-ADPr at telomeres and its impact on telomere function.
Main Methods:
- Investigated DNA-ADPr at telomeres using PARP1 and TARG1.
- Analyzed the association of DNA-ADPr with lagging strand synthesis and single-stranded DNA.
- Utilized a bacterial DNA ADP-ribosyl-transferase toxin to directly modify telomeric DNA.
Main Results:
- Telomeres are identified as direct targets of DNA-ADPr, catalyzed by PARP1 and removed by TARG1.
- DNA-ADPr is coupled to lagging telomere DNA synthesis, occurring at unligated Okazaki fragments and 3' overhangs.
- TARG1 deficiency leads to persistent DNA-ADPr and subsequent telomere shortening, while unhydrolyzed DNA-linked ADP-ribose impairs telomere replication and integrity.
Conclusions:
- Telomeres are regulated by PARP1 and TARG1-mediated DNA-ADPr.
- Proper turnover of DNA-ADPr is critical for telomere replication and integrity, thus essential for sustained genome stability.
Related Concept Videos
02:41Telomeres and Telomerase
23.3K
In eukaryotic DNA replication, a single-stranded DNA fragment remains at the end of a chromosome after the removal of the final primer. This section of DNA cannot be replicated in the same manner as the rest of the strand because there is no 3’ end to which the newly synthesized DNA can attach. This non-replicated fragment results in gradual loss of the chromosomal DNA during each cell duplication. Additionally, it can induce a DNA damage response by enzymes that recognize single-stranded...
23.3K
02:37DNA Damage can Stall the Cell Cycle
9.1K
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...
9.1K
01:29Replication in Eukaryotes
13.7K
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.
Many Proteins Orchestrate Replication at the Origin
Eukaryotic replication follows many of the same...
Many Proteins Orchestrate Replication at the Origin
Eukaryotic replication follows many of the same...
13.7K
02:15Replicative Cell Senescence
3.6K
Replicative cell senescence is a property of cells that allows them to divide a finite number of times throughout the organism's lifespan while preventing excessive proliferation. Replicative senescence is associated with the gradual loss of the telomere — short, repetitive DNA sequences found at the end of the chromosomes. Telomeres are bound by a group of proteins to form a protective cap on the ends of chromosomes. Embryonic stem cells express telomerase — an enzyme that adds...
3.6K
02:37Restarting Stalled Replication Forks
5.8K
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,...
5.8K
01:23Negative Regulator Molecules
35.3K
Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
35.3K