Home » Posts tagged 'DNA'

Tag Archives: DNA

Recent Article Published: Unique H-bonding of Adenine with oxidatively damaged base 8-oxoguanosine enables specific recognition and repair by DNA glycosylase MutY.

Recent Article Published by Sheila David’s Lab: Unique Hydrogen Bonding of Adenine with the Oxidatively Damaged Base 8-Oxoguanine Enables Specific Recognition and Repair by DNA Glycosylase MutY.

Majumdar, C.; Mckibbin, P.L.; Krajewski, A.E.; Manlove, A.H.; Lee, J.K.; David, S.S.
J. Am. Soc. 2020. 142, 48, 20340–20350.

      DNA repair protein MutY employs specific interactions to differentiate OG:A basepairs from canonical G:C and T:A basepairs. Prior work from our lab has focused on understanding the structural requirements of OG on lesion recognition and catalysis, and we have shown that MutY relies on the exocyclic 2-amino group of OG to identify and distinguish OG:A from other basepairs. Additionally, we’ve shown that OG binding induces conformational changes that influence A excision.

     This new work uses structure-activity relationships (SARs) to identify the structural features of A that influence OG:A recognition, verification, base excision, and overall cellular repair. We correlate observed in vitro MutY activity on A analogue substrates with their experimental and calculated acidities to provide mechanistic insight into the factors influencing MutY base excision efficiency. Our results herein can be used to guide future design of MutY/MUTYH specific probes to monitor the activity, or lack thereof, of MutY/MUTYH variants. These results can also applied toward the development of MUTY/MUTYH specific inhibitors that may find utility in cancer therapeutics.

Click on the link or graphical abstract to find out more!

https://pubs.acs.org/doi/abs/10.1021/jacs.0c06767#

 

New Manuscript Published: The Zinc Linchpin Motif in the DNA Repair Glycosylase MUTYH: Identifying the Zn2+ Ligands and Roles in Damage Recognition and Repair.

New Manuscript Published: The Zinc Linchpin Motif in the DNA Repair Glycosylase MUTYH: Identifying the Zn2+ Ligands and Roles in Damage Recognition and Repair.

A recent publication from the David, Siegel and Lim (Academia Sinica, Taiwan) labs (Nuñez et al., JACS, 2018) provides insight into the coordination sphere and critical role of a Zn2+ metal binding site in the DNA repair glycosylase MUTYH. Genome database mining and sequence alignment of MUTYH orthologs, along with computational modeling, identified and supported Zn2+ ligation by four Cys residues. Three of the Cys residues lie in an interdomain connector region unique to mammalian MutY enzymes, while the 4th Cys is located in close proximity to the Fe-S cluster DNA binding domain. The functional consequences of reduced Zn2+ chelation on MUTYH-mediated DNA repair activity evaluated using a battery of in vitro and cell-based assays revealed the importance of Zn-coordination in recognition of the damaged DNA substrate. The critical nature of the “Zinc Linchpin Motif” suggests additional functions unique to higher organisms in damage signaling and crosstalk with other DNA repair pathways.

More information at https://pubs.acs.org/doi/10.1021/jacs.8b06923.

Source:

J. Am. Chem. Soc. 2018, 140, 13260-13271.

Keywords: #Muty #Mutyh #BER #DNA #DNARepair #ZincLinchpinMotif #Zn2+ #8OG #DavidLab #UCDavis

 

 

 

 

 

New Manuscript Published: Selective base excision repair of DNA damage by the non‐base‐flipping DNA glycosylase AlkC.

New Manuscript Published: Selective base excision repair of DNA damage by the non‐base‐flipping DNA glycosylase AlkC.

The preservation of genomic integrity performed by DNA repair machinery is crucial for living organisms, and malfunctions in DNA repair machinery can have far-reaching and devastating effects on a cell’s ability to attain precise DNA replication, properly regulate cell differentiation and self-renewal, and to regulate cell growth and apoptosis, among other important cellular functions. Mutations of critical residues in DNA repair proteins can drastically reduce DNA repair capability in cells, allowing for a build-up of genomic mutations. Inherited variants in DNA repair proteins such as glycosylase MUTYH have been linked to a predisposition to tumors in patients with disease MUTYH Associated Polyposis (MAP). The David Lab is interested in delineating DNA repair mechanisms to help shed light on the etiology of cancer and other diseases, providing mechanistic and structural information that may be used, for example, to design drug molecules targeting DNA repair proteins.

New work from the David Lab examined the selective base excision repair of DNA damage by the non-base-flipping DNA glycosylase AlkC, which primarily targets alkylated-DNA damage product N3-methyladenine (3mA). This work details how AlkC selects for and excises 3mA with its non-base-flipping mechanism. The authors carried out a comprehensive phylogenetic, biochemical, and structural comparison of AlkC and AlkD proteins for comparison, which shows, notably, characteristics important for substrate specificity and why bulkier substrates are not preferred. Interestingly, AlkC’s excision mechanism involves using HEAT-like repeat domains and in most cases Ig-like domains to introduce a kink in the target DNA, helping to expose the target nucleobase, allowing for subsequent insertion of the enzyme active site to excise its target.

Click here to read more about AlkC’s non-base-flipping mechanism.

 

Source:

The EMBO Journal 

 

Just Accepted Manuscript: Structure Activity Relationships Reveal Key Features of 8-Oxoguanine:Adenine Mismatch Detection by the MutY DNA Glycosylase


7/20/2017

The recently accepted manuscript, Structure Activity Relationships Reveal Key Features of 8-Oxoguanine:Adenine Mismatch Detection by the MutY DNA Glycosylase, was accepted for publication in ACS Chemical Biology.

MutY, remarkably, is able to specifically recognize and initiate repair of target OG:A mismatches from among a vast sea of natural DNA. To help reveal molecular features of OG that are critical for MutY recognition, this work explored the effects of systematic OG:A substrate alterations on MutY recognition in a cellular context. OG analogs were synthesized, assembled into OG:A modified oligonucleotides, and structure activity relationships were investigated using binding and cellular repair assays. Read the article to find out more about how specific OG modifications effect MutY glycosylase activity. Click here for the article: http://pubs.acs.org/doi/abs/10.1021/acschembio.7b00389.

 

Keywords: #Muty #DNA #DNARepair #BER #ModifiedNucleosides #Enzymes #8OG #DavidLab #UCDavis #glycosylase

Congratulations to Doug Banda and coworkers!


5/31/2017

Congratulations to David Lab authors Doug, Nicole, Michael, and Katie on their recently released article, “Repair of 8-OXOG:A Mismatches by the MUTYH Glycosylase: Mechanisms, Metals and Medicine,” in Free Radical Biology and Medicine! The final version of the article is now available online.

Link to their new article here: https://authors.elsevier.com/a/1V8Lr3AkHAI6DS.


 

RSS Science Daily News

  • Fitness trackers are failing millions — this fix could change everything June 20, 2025
    Fitness trackers often fail people with obesity by underestimating their energy burn, leading to discouraging results and misguided health data. A scientist's frustrating experience in an exercise class with his mother-in-law where her effort wasn t reflected on the fitness leaderboard sparked a breakthrough. His team at Northwestern developed a new open-source smartwatch algorithm that […]
  • One shot to stop HIV: MIT's bold vaccine breakthrough June 19, 2025
    Researchers from MIT and Scripps have unveiled a promising new HIV vaccine approach that generates a powerful immune response with just one dose. By combining two immune-boosting adjuvants alum and SMNP the vaccine lingers in lymph nodes for nearly a month, encouraging the body to produce a vast array of antibodies. This one-shot strategy could […]
  • How life endured the Snowball Earth: Evidence from Antarctic meltwater ponds June 19, 2025
    During Earth's ancient Snowball periods, when the entire planet was wrapped in ice, life may have endured in tiny meltwater ponds on the surface of equatorial glaciers. MIT researchers discovered that these watery refuges could have supported complex eukaryotic life, serving as sanctuaries for survival amid extreme conditions. Their investigation into Antarctic melt ponds revealed […]
  • Microscopic heist: How lung bacteria forge weapons to steal iron and survive June 19, 2025
    Researchers investigating the enigmatic and antibiotic-resistant Pandoraea bacteria have uncovered a surprising twist: these pathogens don't just pose risks they also produce powerful natural compounds. By studying a newly discovered gene cluster called pan, scientists identified two novel molecules Pandorabactin A and B that allow the bacteria to steal iron from their environment, giving them […]
  • Massive thread of hot gas found linking galaxies — and it’s 10 times the mass of the Milky Way June 19, 2025
    Astronomers have uncovered a colossal, searing-hot filament of gas linking four galaxy clusters in the Shapley Supercluster a discovery that could finally solve the mystery of the Universe s missing matter. This giant thread, 10 times the mass of the Milky Way and stretching 23 million light-years, is one of the best confirmations yet of […]

Contact:

Dr. Sheila S. David
ssdavid@ucdavis.edu
(530)-752-4280

Department of Chemistry
One Shields Ave.
Davis, CA 95616