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

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.

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

Circulation ◽

10.1161/circ.132.suppl_3.15981 ◽

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.

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Faculty Opinions recommendation of DNA damage response pathway uses histone modification to assemble a double-strand break-specific cohesin domain.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1023043.265685 ◽

2004 ◽

Author(s):

Tatsuya Hirano

Keyword(s):

Dna Damage ◽

Histone Modification ◽

Dna Damage Response ◽

Strand Break ◽

Double Strand Break ◽

Damage Response ◽

Dna Damage Response Pathway

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Faculty Opinions recommendation of DNA damage response pathway uses histone modification to assemble a double-strand break-specific cohesin domain.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1023043.281697 ◽

2005 ◽

Author(s):

Susan Forsburg

Keyword(s):

Dna Damage ◽

Histone Modification ◽

Dna Damage Response ◽

Strand Break ◽

Double Strand Break ◽

Damage Response ◽

Dna Damage Response Pathway

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DNA Damage Response Pathway Uses Histone Modification to Assemble a Double-Strand Break-Specific Cohesin Domain

Molecular Cell ◽

10.1016/j.molcel.2004.11.027 ◽

2004 ◽

Vol 16 (6) ◽

pp. 991-1002 ◽

Cited By ~ 386

Author(s):

Elçin Ünal ◽

Ayelet Arbel-Eden ◽

Ulrike Sattler ◽

Robert Shroff ◽

Michael Lichten ◽

...

Keyword(s):

Dna Damage ◽

Histone Modification ◽

Dna Damage Response ◽

Strand Break ◽

Double Strand Break ◽

Damage Response ◽

Dna Damage Response Pathway

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Characterization of the role of the DNA damage response pathway in parvoviral replication

10.32469/10355/15925 ◽

2012 ◽

Author(s):

Richard Adeyemi

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Damage Response ◽

Dna Damage Response Pathway

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

Molecular and Cellular Biology ◽

10.1128/mcb.00460-13 ◽

2013 ◽

Vol 33 (16) ◽

pp. 3286-3298 ◽

Cited By ~ 19

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.

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