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 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 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

Abstract 15981: DNA Single-strand Break-induced DNA Damage Response Causes Heart Failure

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Tomoaki Higo ◽  
Atsuhiko Naito ◽  
Masato Shibamoto ◽  
Jong-Kook Lee ◽  
Shungo Hikoso ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dna Damage ◽  
Inflammatory Cytokines ◽  
Dna Damage Response ◽  
Nuclear Translocation ◽  
Pressure Overload ◽  
Strand Break ◽  
Single Strand Break ◽  
Failing Heart ◽  
Damage Response

Introduction: The DNA damage response (DDR) pathway is activated upon DNA damage. In mitotic cells, the DDR plays essential role in maintaining genomic stability and preventing cancer formation. DNA damage and activation of the DDR are also observed in the post-mitotic cardiomyocytes of patients with end-stage heart failure, however, their roles in the pathogenesis of heart failure remains elusive. Methods and Results: We performed transverse aortic constriction (TAC) operation to produce mice model of pressure-overload induced heart failure. Alkaline- and neutral- comet assay revealed that unrepaired DNA single-strand break (SSB), not double-strand break, is accumulated in cardiomyocytes of the failing heart. Mice with cardiomyocyte-specific deletion of XRCC1, a scaffold protein essential for SSB repair, exhibited more severe heart failure and higher mortality after TAC operation. Knockdown of Xrcc1 using siRNA produced SSB accumulation in cardiomyocytes and SSB accumulation induced persistent DDR through activation of ataxia telangiectasia mutated (ATM) kinase. Activated ATM also induced nuclear translocation of NF-κB and increased the expression of inflammatory cytokines. Activation of DDR, nuclear translocation of NF-κB, and increased expression of inflammatory cytokines were also observed in the failing heart and were enhanced in the heart of cardiomyocyte-specific XRCC1 knockout mice. Conclusions: Unrepaired DNA SSB accumulates in post-mitotic cardiomyocytes and plays a pathogenic role in pressure overload-induced heart failure. Approaches that promote efficient SSB repair or suppress aberrant activation of DDR pathway may become a novel therapeutic strategy against heart failure.

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.

Abstract 53: Pathogenic role of DNA Single Strand Break Accumulation in Heart Failure

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Tomoaki Higo ◽  
Atsuhiko Naito ◽  
Yasushi Sakata ◽  
Issei Komuro
Keyword(s):  
Heart Failure ◽  
Dna Damage ◽  
Nuclear Dna ◽  
Nuclear Translocation ◽  
Strand Break ◽  
Single Strand ◽  
Single Strand Break ◽  
Failing Heart ◽  
Mitotic Cells

Various environmental stress including reactive oxygen species (ROS) causes nuclear DNA damage. Increased production of ROS is observed in the failing heart and is considered as one of the causes of heart failure. Accumulating evidences suggest the presence of DNA damage in the failing heart, however, mechanistic link that connects DNA damage and heart failure remains elusive. Here, we show that DNA single strand break (SSB) accumulates in the failing heart and that SSB accumulation induces cell-autonomous inflammation through activation of DNA damage response (DDR) signaling pathway. Using alkaline- and neutral comet assay, we found that SSB is increased in the failing heart of pressure overload. Using in vitro model, we found that SSB accumulation activates ataxia talengiectasia mutated (ATM) kinase, which in turn induces nuclear translocation of NF-kB and increases the expression of inflammatory cytokines. Our findings suggest that SSB accumulation in cardiomyocytes plays an important role in the pathogenesis of heart failure by activating DDR pathway and subsequent cell-autonomous inflammation. SSB accumulation is supposed to be characteristic to post-mitotic cells like cardiomyocytes because unrepaired SSB usually develops into DNA double strand break and lead to catastrophic cellular death in mitotic cells. Approaches targeting efficient SSB repair or DDR pathway may become a novel therapeutic strategy against heart failure.

scholarly journals Sites of Acetylation on Newly Synthesized Histone H4 Are Required for Chromatin Assembly and DNA Damage Response Signaling

2013 ◽  
Vol 33 (16) ◽  
pp. 3286-3298 ◽  
Author(s):  
Zhongqi Ge ◽  
Devi Nair ◽  
Xiaoyan Guan ◽  
Neha Rastogi ◽  
Michael A. Freitas ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Histone H3 ◽  
Model Organism ◽  
Strand Break ◽  
Chromatin Assembly ◽  
Histone H4 ◽  
Histone H4 Acetylation ◽  
Damage Response ◽  
A Site

The best-characterized acetylation of newly synthesized histone H4 is the diacetylation of the NH2-terminal tail on lysines 5 and 12. Despite its evolutionary conservation, this pattern of modification has not been shown to be essential for either viability or chromatin assembly in any model organism. We demonstrate that mutations in histone H4 lysines 5 and 12 in yeast confer hypersensitivity to replication stress and DNA-damaging agents when combined with mutations in histone H4 lysine 91, which has also been found to be a site of acetylation on soluble histone H4. In addition, these mutations confer a dramatic decrease in cell viability when combined with mutations in histone H3 lysine 56. We also show that mutation of the sites of acetylation on newly synthesized histone H4 results in defects in the reassembly of chromatin structure that accompanies the repair of HO-mediated double-strand breaks. This defect is not due to a decrease in the level of histone H3 lysine 56 acetylation. Intriguingly, mutations that alter the sites of newly synthesized histone H4 acetylation display a marked decrease in levels of phosphorylated H2A (γ-H2AX) in chromatin surrounding the double-strand break. These results indicate that the sites of acetylation on newly synthesized histones H3 and H4 can function in nonoverlapping ways that are required for chromatin assembly, viability, and DNA damage response signaling.

scholarly journals Schizosaccharomyces pombe KAT5 contributes to resection and repair of a DNA double strand break

Genetics ◽  
2021 ◽  
Author(s):  
Tingting Li ◽  
Ruben C Petreaca ◽  
Susan L Forsburg
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Chromatin Remodeling ◽  
Dna Damage Response ◽  
Histone Acetyltransferase ◽  
Strand Break ◽  
Double Strand Break ◽  
Dna Damage Checkpoint ◽  
Dna Double Strand Break ◽  
Damage Response

Abstract Chromatin remodeling is essential for effective repair of a DNA double strand break. KAT5 (S. pombe Mst1, human TIP60) is a MYST family histone acetyltransferase conserved from yeast to humans that coordinates various DNA damage response activities at a DNA double strand break (DSB), including histone remodeling and activation of the DNA damage checkpoint. In S. pombe, mutations in mst1+ causes sensitivity to DNA damaging drugs. Here we show that Mst1 is recruited to DSBs. Mutation of mst1+ disrupts recruitment of repair proteins and delays resection. These defects are partially rescued by deletion of pku70, which has been previously shown to antagonize repair by homologous recombination. These phenotypes of mst1 are similar to pht1-4KR, a non-acetylatable form of histone variant H2A.Z, which has been proposed to affect resection. Our data suggest that Mst1 functions to direct repair of DSBs towards homologous recombination pathways by modulating resection at the double strand break.

scholarly journals DNA Damage-Induced Phosphorylation of TRF2 Is Required for the Fast Pathway of DNA Double-Strand Break Repair

2009 ◽  
Vol 29 (13) ◽  
pp. 3597-3604 ◽  
Author(s):  
Nazmul Huda ◽  
Hiromi Tanaka ◽  
Marc S. Mendonca ◽  
David Gilley
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Functional Role ◽  
Strand Break ◽  
Telomere Maintenance ◽  
Telomeric Dna ◽  
Dsb Repair ◽  
Dna Double Strand Break ◽  
Damage Response ◽  
Fast Pathway

ABSTRACT Protein kinases of the phosphatidylinositol 3-kinase-like kinase family, originally known to act in maintaining genomic integrity via DNA repair pathways, have been shown to also function in telomere maintenance. Here we focus on the functional role of DNA damage-induced phosphorylation of the essential mammalian telomeric DNA binding protein TRF2, which coordinates the assembly of the proteinaceous cap to disguise the chromosome end from being recognized as a double-stand break (DSB). Previous results suggested a link between the transient induction of human TRF2 phosphorylation at threonine 188 (T188) by the ataxia telangiectasia mutated protein kinase (ATM) and the DNA damage response. Here, we report evidence that X-ray-induced phosphorylation of TRF2 at T188 plays a role in the fast pathway of DNA DSB repair. These results connect the highly transient induction of human TRF2 phosphorylation to the DNA damage response machinery. Thus, we find that a protein known to function in telomere maintenance, TRF2, also plays a functional role in DNA DSB repair.

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 The nucleoporin 153, a novel factor in double-strand break repair and DNA damage response

Oncogene ◽  
2012 ◽  
Vol 31 (45) ◽  
pp. 4803-4809 ◽  
Author(s):  
C Lemaître ◽  
B Fischer ◽  
A Kalousi ◽  
A-S Hoffbeck ◽  
J Guirouilh-Barbat ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Strand Break ◽  
Double Strand Break ◽  
Double Strand Break Repair ◽  
Damage Response ◽  
Break Repair
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