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Key molecular enzyme locates sites of DNA breaks

Research has revealed the function of a widely shared component of the enzyme Zf-GRF domain, as a critical molecular tool needed to begin DNA repair processes.

The DNA of living organisms needs constant maintenance. Every cell is under a state of siege from reactive oxygen compounds and ions that constantly assault and damage a cell's molecules — especially its DNA.

Oxidative damage to DNA is estimated at 10,000 times per day per cell.

For life to survive this molecular battlefield, cells have evolved counter measures. Among them, a suite of complex molecules that detect oxidative damage in sections of DNA. These complex molecules target damaged areas to initiate elaborate engineering operations and fix the problem. Scientists are constantly working to identify and reconstruct repair and signaling mechanics that control DNA damage.

Now, a specific protein — the Zf-GRF domain — a component of APE2, a DNA-repair and DNA damage response enzyme has been identified for its precise role. The Zf-GRF domain is common in a number of DNA maintenance molecules.

New research shows that Zf-GRF performs a critical DNA binding function to help enzymes align to a single strand of DNA.

The new study appeared in the Proceedings of the National Academy of Sciences (PNAS) on December 27, 2016.

This finding is a result of efforts of two teams, one headed by Shan Yan from the Department of Biological Sciences at the University of North Carolina at Charlotte, and the second headed by R. Scott Williams from the Genome Integrity and Structural Biology Laboratory at the National Institute of Environmental Health Sciences (NIEHS) in the National Institutes of Health.

"We study APE2, which plays an important role in repairing DNA following oxidative stress. We are trying to understand the structure and function of this enzyme because it's [features are] not well characterized, but it plays a central role in the cellular response to oxidative DNA damage."

Shan Yan PhD, Department of Biological Sciences, University of North Carolina at Charlotte, USA.

Within the different APE2 domains is one least understood called Zf-GRF. Zf-GRF is specifically attracted to single strand DNA. If it does not bind to a strand, APE2 can't begin its catalytic activity and move in the right direction on that strand in order to repair it.

Yan's group also found the Zf-GRF domain in several other proteins. In all cases it had a "claw-like" structure of proteins surrounding a zinc molecule. All of these Zf-GRF domains were almost identical or "highly conserved."

Williams points out that as the APE2 molecular tool is found eveywhere and is uniform in the Zf-GRF structure, it must play a very useful and critical role in controlling enzymes.

"Though it's a very small domain - about 50 amino acids - it's highly conserved [remaining essentially unchanged] in evolution. This enzyme domain is the same across many species, which implies that it's important. It is also found not only in APE2, but in many other enzymes, including important DNA metabolism enzymes such as Topoisomerase 3A and NEIL3.

"The APE2 DNA processing activity is necessary for activating "cellular checkpoints". An alarm is signaled when DNA damage is detected, and helps to prevent further damage from occurring, while making it possible for a cell to fix these toxic lesions.

"If left in an unrepaired and un-signaled state, such oxidative DNA damage can be a major contributing factor to cancer progression, amongst other maladies."

R. Scott Williams PhD, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA

Zf-GRF domains are found in more than 100 eukaryotic architectures, including key proteins modulating DNA damage response and transcription. We establish the apurinic/apyrimidinic endonuclease 2 (APE2) Zf-GRF domain as a prototypical member of the Zf-GRF class of nucleic acid-binding modules, and through structural analysis reveal that the APE2 protein is composed of a compacted three-stranded β-sheet and a CHCC Zn2+-binding site, harboring structure-specific ssDNA-binding activity. Notably, the ssDNA-binding region of APE2 Zf-GRF is required for the 3′-5′ end resection of oxidative DNA damage and activation of the ATR-Chk1 DNA damage response pathway following oxidative stress. This distinct regulatory mechanism of APE2 exonuclease activity by ssDNA binding via Zf-GRF may extend to other Zf-GRF–containing proteins.

The Xenopus laevis APE2 (apurinic/apyrimidinic endonuclease 2) nuclease participates in 3′-5′ nucleolytic resection of oxidative DNA damage and activation of the ATR-Chk1 DNA damage response (DDR) pathway via ill-defined mechanisms. Here we report that APE2 resection activity is regulated by DNA interactions in its Zf-GRF domain, a region sharing high homology with DDR proteins Topoisomerase 3α (TOP3α) and NEIL3 (Nei-like DNA glycosylase 3), as well as transcription and RNA regulatory proteins, such as TTF2 (transcription termination factor 2), TFIIS, and RPB9. Biochemical and NMR results establish the nucleic acid-binding activity of the Zf-GRF domain. Moreover, an APE2 Zf-GRF X-ray structure and small-angle X-ray scattering analyses show that the Zf-GRF fold is typified by a crescent-shaped ssDNA binding claw that is flexibly appended to an APE2 endonuclease/exonuclease/phosphatase (EEP) catalytic core. Structure-guided Zf-GRF mutations impact APE2 DNA binding and 3′-5′ exonuclease processing, and also prevent efficient APE2-dependent RPA recruitment to damaged chromatin and activation of the ATR-Chk1 DDR pathway in response to oxidative stress in Xenopus egg extracts. Collectively, our data unveil the APE2 Zf-GRF domain as a nucleic acid interaction module in the regulation of a key single-strand break resection function of APE2, and also reveal topologic similarity of the Zf-GRF to the zinc ribbon domains of TFIIS and RPB9.

Bret D. Wallace, Geoffrey A. Mueller, Timothy Chang, Sara N. Andres, Jessica L. Wojtaszek, Eugene F. DeRose, C. Denise Appel, Robert E. London, and R. Scott Williams from the Genome Integrity and Structural Biology Laboratory at NIEHS/NIH, and Zachary Berman, Yunfeng Lin and Shan Yan from the Department of Biological Sciences at UNC Charlotte.

The research was supported by funds from UNC Charlotte and NIGMS/NIH (grant numbers R15 GM101571 and R15 GM114713) and NIEHS/NIH (grant numbers 1Z01ES102765 and 1Z01ES050111).
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In the DNA replication process, the two strands who act as a template to synthesise a complementary strand are separated, and the new complementary strand joins each of the initial strands in order to obtain two identical copies of the original DNA molecule.
Image Credit: Phys.org



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