scholarly journals Single-Strand Break End Resection in Genome Integrity: Mechanism and Regulation by APE2

2018 ◽  
Vol 19 (8) ◽  
pp. 2389 ◽  
Author(s):  
Md. Hossain ◽  
Yunfeng Lin ◽  
Shan Yan
Keyword(s):  
Dna Damage ◽  
Genome Instability ◽  
Strand Break ◽  
Single Strand ◽  
Genome Integrity ◽  
Single Strand Break ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Damage Response ◽  
End Resection

DNA single-strand breaks (SSBs) occur more than 10,000 times per mammalian cell each day, representing the most common type of DNA damage. Unrepaired SSBs compromise DNA replication and transcription programs, leading to genome instability. Unrepaired SSBs are associated with diseases such as cancer and neurodegenerative disorders. Although canonical SSB repair pathway is activated to repair most SSBs, it remains unclear whether and how unrepaired SSBs are sensed and signaled. In this review, we propose a new concept of SSB end resection for genome integrity. We propose a four-step mechanism of SSB end resection: SSB end sensing and processing, as well as initiation, continuation, and termination of SSB end resection. We also compare different mechanisms of SSB end resection and DSB end resection in DNA repair and DNA damage response (DDR) pathways. We further discuss how SSB end resection contributes to SSB signaling and repair. We focus on the mechanism and regulation by APE2 in SSB end resection in genome integrity. Finally, we identify areas of future study that may help us gain further mechanistic insight into the process of SSB end resection. Overall, this review provides the first comprehensive perspective on SSB end resection in genome integrity.

scholarly journals APE2 promotes DNA damage response pathway from a single-strand break

2018 ◽  
Vol 46 (5) ◽  
pp. 2479-2494 ◽  
Author(s):  
Yunfeng Lin ◽  
Liping Bai ◽  
Steven Cupello ◽  
Md Akram Hossain ◽  
Bradley Deem ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Strand Break ◽  
Single Strand ◽  
Single Strand Break ◽  
Damage Response ◽  
Dna Damage Response Pathway

scholarly journals DNA damage response by single-strand breaks in terminally differentiated muscle cells and the control of muscle integrity

2012 ◽  
Vol 19 (11) ◽  
pp. 1741-1749 ◽  
Author(s):  
P Fortini ◽  
C Ferretti ◽  
B Pascucci ◽  
L Narciso ◽  
D Pajalunga ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Muscle Cells ◽  
Single Strand ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Damage Response

scholarly journals Bridging of nucleosome-proximal DNA double-strand breaks by PARP2 enhances its interaction with HPF1

2019 ◽  
Author(s):  
Guillaume Gaullier ◽  
Genevieve Roberts ◽  
Uma M. Muthurajan ◽  
Samuel Bowerman ◽  
Johannes Rudolph ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Genome Instability ◽  
Structural Information ◽  
Regulatory Protein ◽  
Strand Break ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Damage Response

AbstractPoly(ADP-ribose) Polymerase 2 (PARP2) is one of three DNA-dependent PARPs involved in the detection of DNA damage. Upon binding to DNA double-strand breaks, PARP2 uses nicotinamide adenine dinucleotide to synthesize poly(ADP-ribose) (PAR) onto itself and other proteins, including histones. PAR chains in turn promote the DNA damage response by recruiting downstream repair factors. These early steps of DNA damage signaling are relevant for understanding how genome integrity is maintained and how their failure leads to genome instability or cancer. There is no structural information on DNA double-strand break detection in the context of chromatin. Here we present a cryo-EM structure of two nucleosomes bridged by human PARP2 and confirm that PARP2 bridges DNA ends in the context of nucleosomes bearing short linker DNA. We demonstrate that the conformation of PARP2 bound to damaged chromatin provides a binding platform for the regulatory protein Histone PARylation Factor 1 (HPF1), and that the resulting HPF1•PARP2•nucleosome complex is enzymatically active. Our results contribute to a structural view of the early steps of the DNA damage response in chromatin.

scholarly journals DNA single-strand break-induced DNA damage response causes heart failure

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Tomoaki Higo ◽  
Atsuhiko T. Naito ◽  
Tomokazu Sumida ◽  
Masato Shibamoto ◽  
Katsuki Okada ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Strand Break ◽  
Single Strand ◽  
Single Strand Break ◽  
Damage Response

scholarly journals Reduced DNA repair during differentiation of a myogenic cell line.

1976 ◽  
Vol 70 (3) ◽  
pp. 685-691 ◽  
Author(s):  
A C Chan ◽  
I G Walker
Keyword(s):  
Strand Break ◽  
Post Treatment ◽  
Single Strand ◽  
Repair Synthesis ◽  
Single Strand Break ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Before And After ◽  
Dna Strands ◽  
A Minor

Repair synthesis induced by 4-nitroquinoline-1-oxide (4NQO) in L6 myoblasts before and after cellular fusion was measured by [3H] thymidine incorporation into unreplicated DNA. The level of repair synthesis was reuced after the cells had fused into myotubes. The terminal addition of radioactive nucleotides into DNA strands occurred only to a minor extent, and the dilution of [3H] thymidine by intracellular nucleotide pools was shown not to be responsible for the observed difference in repair synthesis, Both the initial rate and the overall incorporation of [3H] thymidine were found to be 50% lower in the myotubes. 4NQO treatment of myoblasts and myotubes induced modifications in the DNA which were observed as single-strand breaks during alkaline sucrose sedimentation. After the myoblasts were allowed a post-treatment incubation, most of the single-strand breaks were not longer apparent. In contrast, a post-treatment incubation of myotubes did not change the extent of single-strand breakage seen. Both myoblasts and myotubes were equally effective in repairing single-strand breaks induced by X radiation. It would appear that when myoblasts fuse, a repair enzyme activity is lost, probably an endonuclease that recognizes one of the 4 NQO modifications of DNA. The result observed is a partial loss of repair synthetic ability and a complete loss of ability to remove the modification that appears as a single-strand break in alkali.

scholarly journals Pathogenic role of DNA single-strand break accumulation and DNA damage response in pressure overload-induced heart failure

2018 ◽  
Vol WCP2018 (0) ◽  
pp. OR2-4
Author(s):  
Atsuhiko T. Naito ◽  
Tomoaki Higo ◽  
Hiroko Izumi-Nakaseko ◽  
Kentaro Ando ◽  
Mihoko Hagiwara-Nagasawa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Pressure Overload ◽  
Strand Break ◽  
Single Strand ◽  
Pathogenic Role ◽  
Single Strand Break ◽  
Damage Response

scholarly journals Neuronal Enhancers are Hotspots For DNA Single-Strand Break Repair

2020 ◽  
Author(s):  
Wei Wu ◽  
Sarah E. Hill ◽  
William J. Nathan ◽  
Jacob Paiano ◽  
Kenta Shinoda ◽  
...  
Keyword(s):  
Dna Repair ◽  
Genome Stability ◽  
Cell Types ◽  
Strand Break ◽  
Single Strand ◽  
Single Strand Break ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Single Strand Break Repair ◽  
The Central Nervous System

Genome stability is essential for all cell types. However, defects in DNA repair frequently lead to neurodevelopmental and neurodegenerative diseases, underscoring the particular importance of DNA repair in long-lived post-mitotic neurons. The neuronal genome is subjected to a constant barrage of endogenous DNA damage due to high levels of oxidative metabolism in the central nervous system. Surprisingly, we know little about the identity of the lesion(s) that accumulate in neurons and whether they accrue throughout the genome or at specific loci. Here, we show that neurons, but not other post-mitotic cells, accumulate unexpectedly high numbers of DNA single-strand breaks (SSBs) at specific sites within the genome. These recurrent SSBs are found within enhancers, and trigger DNA repair through recruitment and activation of poly(ADP-ribose) polymerase-1 (PARP1) and XRCC1, the central SSB repair scaffold protein. Notably, deficiencies in PARP1, XRCC1, or DNA polymerase β elevate the localized incorporation of nucleotides, suggesting that the ongoing DNA synthesis at neuronal enhancers involves both short-patch and long-patch SSB repair processes. These data reveal unexpected levels of localized and continuous DNA single-strand breakage in neurons, suggesting an explanation for the neurodegenerative phenotypes that occur in patients with defective SSB repair.

Protein–protein interactions during mammalian DNA single-strand break repair

2003 ◽  
Vol 31 (1) ◽  
pp. 247-251 ◽  
Author(s):  
K.W. Caldecott
Keyword(s):  
Protein Interactions ◽  
Mammalian Cells ◽  
Strand Break ◽  
Double Strand Breaks ◽  
Single Strand ◽  
Protein Protein Interactions ◽  
Single Strand Break ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Single Strand Break Repair

The genetic stability of living cells is continually threatened by endogenous reactive oxygen species and other genotoxic molecules. Of particular threat are the thousands of single-strand breaks that arise in each cell every day. If left unrepaired, such breaks can give rise to potentially clastogenic or lethal chromosomal double-strand breaks. This article summarizes our current understanding of how mammalian cells detect and repair single strand breaks, and provides insights into novel polypeptide components of this process.

scholarly journals APE1 senses DNA single-strand breaks for repair and signaling

2019 ◽  
Vol 48 (4) ◽  
pp. 1925-1940 ◽  
Author(s):  
Yunfeng Lin ◽  
Jude Raj ◽  
Jia Li ◽  
Anh Ha ◽  
Md Akram Hossain ◽  
...  
Keyword(s):  
Dna Damage ◽  
Signaling Pathways ◽  
Somatic Tissue ◽  
Single Strand ◽  
Exonuclease Activity ◽  
Cancer Etiology ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
End Resection

Abstract DNA single-strand breaks (SSBs) represent the most abundant type of DNA damage. Unrepaired SSBs impair DNA replication and transcription, leading to cancer and neurodegenerative disorders. Although PARP1 and XRCC1 are implicated in the SSB repair pathway, it remains unclear how SSB repair and SSB signaling pathways are coordinated and regulated. Using Xenopus egg extract and in vitro reconstitution systems, here we show that SSBs are first sensed by APE1 to initiate 3′–5′ SSB end resection, followed by APE2 recruitment to continue SSB end resection. Notably, APE1’s exonuclease activity is critical for SSB repair and SSB signaling pathways. An APE1 exonuclease-deficient mutant identified in somatic tissue from a cancer patient highlighted the significance of APE1 exonuclease activity in cancer etiology. In addition, APE1 interacts with APE2 and PCNA, although PCNA is dispensable for APE1’s exonuclease activity. Taken together, we propose a two-step APE1/APE2-mediated mechanism for SSB end resection that couples DNA damage response with SSB repair in a eukaryotic system.

scholarly journals Effects of variation in glutathione peroxidase activity on DNA damage and cell survival in human cells exposed to hydrogen peroxide and t-butyl hydroperoxide

1990 ◽  
Vol 271 (1) ◽  
pp. 17-23 ◽  
Author(s):  
B E Sandström ◽  
S L Marklund
Keyword(s):  
Glutathione Peroxidase ◽  
Cell Survival ◽  
Peroxidase Activity ◽  
Strand Break ◽  
Single Strand ◽  
Glutathione Peroxidase Activity ◽  
Single Strand Break ◽  
Strand Breaks ◽  
Butyl Hydroperoxide ◽  
Single Strand Breaks

The selenium-dependent glutathione peroxidase activities of two human cell lines, the colon carcinoma HT29 and the mesothelioma P31, cultured in medium containing 2% serum, increased from 195 to 541 and from 94 to 361 units/mg of protein respectively after supplementation with 100 nM-selenite. The catalase activity remained unchanged by this treatment. The effects of the obtained variation in glutathione peroxidase activities were investigated by exposing cells to H2O2 and t-butyl hydroperoxide. Selenite supplementation resulted in a decrease in H2O2-induced DNA single-strand breaks in both HT29 and P31 cells. A small, but significant, decrease in the number of DNA single-strand breaks for low doses (10-50 microM) of t-butyl hydroperoxide was found only in P31 cells and not in HT29 cells. We could detect neither induction of double-strand breaks (detection limit approx. 1000 breaks per cell) nor DNA-protein cross-links after exposing the cells to the two peroxides. In spite of the apparent protective effect of increased glutathione peroxidase activity on DNA single-strand break formation, there were no differences between selenite-supplemented and non-supplemented cells in cell survival after exposure to peroxide.

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