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Recent Article Published by the David Lab: The DNA repair enzyme MUTYH potentiates cytotoxicity of the alkylating agent MNNG by interacting with abasic sites.

Recent Article Published by the David Lab at UC Davis:

The DNA repair enzyme MUTYH potentiates cytotoxicity of the alkylating agent MNNG by interacting with abasic sites

Journal of Biological Chemistry

Inherited defects in the DNA repair gene MUTYH lead to cancer, proof that MUTYH has a critical role in preventing cancer in normal cells. In a new study from the David Lab, MUTYH is shown to have a new role that implicates it in the response to a common class of chemotherapy drugs, alkylating agents (https://www.jbc.org/content/early/2020/01/30/jbc.RA119.010497).

Cancer cells evolve resistance to chemotherapy drugs by a number of mechanisms, including upregulating DNA repair enzymes such as BRCA1, which helps cancer cells survive DNA damaging chemotherapy agents. Surprisingly, MUTYH does not help repair alkylating agent DNA damage, but instead enhance alkylating agent toxicity. This study uncovers the underlying molecular mechanism of this activity, which involves MUTYH stimulating cells to create more toxic DNA repair intermediates. By uncovering the molecular mechanism, this research suggests that MUTYH has both a role in preventing DNA mutations that cause cancer, and a separate role in helping kill cancer cells that are treated with chemotherapy drugs, thus the loss of MUTYH is a “double-whammy”. Tests to determine if cancer patients have normal versus functionally-deficient MUTYH may alter chemotherapy treatment choices if these results can be generalized to clinical practice. 


Citation:

Raetz, A.G.; Banda, D.M.; Ma, X.; Xu, G.; Rajavel, A.N.; McKibbin, P.L.; Lebrilla, C.B.; David, S.S. The DNA repair enzyme MUTYH potentiates cytotoxicity of the alkylating agent MNNG by interacting with abasic sites. J. Biol. Chem. 2020.


doi: 10.1074/jbc.RA119.010497


Keywords:

#sheiladavid #davidlab #mutyh #thedavidlab #ucdavischemistry #cytotoxicity #alkylatingagent #mnng #dna #dnarepair #muty #ucdavis #chemistry #biologicalchemistry #chembio #journalofbiologicalchemistry

David Lab Member Robert Van Ostrand receives Crown Royal Award at Sacramento Kings Salute to Service Night

David Lab Member Robert Van Ostrand was recognized as the Honoree Veteran and received the Crown Royal Award at the Sacramento Kings Salute to Service Night. Robert’s service in the United States Marine Corps from 2005 – 2013 included a deployment to Iraq as an active duty Infantryman, as part of Operation Iraqi Freedom in 2007, which was followed by a transition to Data Networking Specialist as a Reservist in 2010. Robert was selected for this award for his community service for local veterans and for the City of Davis.

 

#davidlab #ucdavis #veterans #vfw6949davis #sheiladavid #robertvanostrand #davis #goags #ucdavischemistry #sacramentokings

 

Robert is presented the Crown Royal Award as the Honoree Veteran at the Sacramento Kings Salute to Service Night
Robert on the big screen showing off the lab!
Robert Accepts the Crown Royal Award
Robert with wife Ashley prior to the game.
Who put him up there?

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

New Article Published: When you’re strange: Unusual features of the MUTYH glycosylase and implications in cancer.

New Article Published: When you’re strange: Unusual features of the MUTYH glycosylase and implications in cancer.

Think MUTYH is a simple adenine glycosylase? Think again. Explore the dizzying diversity of MUTYH interactions to DNA damage response proteins and their implications in cancer in our lab’s newest review by Alan Raetz and Sheila David.

Click here or on the image to link to the article!

When you’re strange: Unusual features of the MUTYH glycosylase and implications in cancer.

Raetz, A.G.; David, S.S. When you’re strange: Unusual features of the MUTYH glycosylase and implications in cancer. DNA Repair201980, 16-25.


#DavidLab #MUTYH #Muty #DNArepair #glycosylase #DDR #cancer #ucdavis #chemistry #chemicalbiology #AlanRaetz #SheilaDavid

The David Laboratory attends CBBA 2019 at UCSF

Members of Sheila David’s Laboratory at UC Davis attended the Chemical Biology in the Bay Area (CBBA) Day on June 1st, 2019, which was hosted by UCSF in San Francisco. This event brought in graduate student presenters from UC Davis, UC Santa Cruz, UC Berkeley, and UCSF. The keynote speaker was Anthony Ogawa from Merck. Merve Demir from our lab presented a research poster titled, “Elucidating Additional Features of 8-Oxo-guanine Recognition and Adenine Excision Mechanism by the DNA Glycosylase MutY.” The speakers were consistently excellent throughout the day, touching on a broad range of topics within the wide world of chemical biology. We all had a great time. Cheers to all of the presenters and volunteers that helped run the conference!

The David Lab @ CBBA; UCSF 2019

Undergraduate Student Spotlight: Madeline Bright

Meet UC Davis Undergraduate Researcher Madeline Bright in our lab’s new Undergraduate Student Spotlight Video! Hear about how she got into undergraduate research and how it will help her career. Undergrads – there is solid advice included on how to join a research lab if you have been thinking about it. Madeline wants to enter into an M.D.-Ph.D. program after her undergraduate work, and is very well on her way towards that goal.

Madeline is a 2nd year Biological Sciences student working in the David Laboratory in the Chemistry Department at UC Davis, and has been with us for over one year. Madeline recently won the 2019 Francesca Miller Undergraduate Research Award at the 2019 Miller Symposium at UC Davis.

Here’s to a Bright future!

 

Beal Lab: There is an Easter Egg in this video for you! Enjoy!

#research #UCDavis #DavidLab #chemistry #dnarepair #undergraduateresearch #millersymposium #biologicalsciences #MadelineBright

The David Lab attends the 2019 Miller Symposium at UC Davis

The Annual R. Bryan Miller Symposium at UC Davis brings top speakers from the field of chemical biology to share cutting edge research results and perspectives on the future of chemical biology research. Dr. Sheila David is the Miller Symposium Committee Chair, and directs the event with the support of faculty, staff, and students. The David Lab attended the 2019 Miller Symposium at UC Davis in full force.

This year’s theme of the Miller Symposium was “Chemistry and Biology of Pain,” and included speakers such as Justin DuBois of Stanford, Alanna Schepartz of Yale, Jon Sack of UC Davis, Ann Weber of Kallyope & Merck, and more.

Dr. Sheila David, Professor of Chemistry and Chair, Miller Symposium Committee

 

Alannah Schepartz of Yale presenting her talk, “How EGFR Works.”

Chandrima Majumdar of the David Lab played a significant role in supporting and organizing the event, and received recognition for her contribution at the awards ceremony.

Chandrima introduces Jian Payandeh of Genentech Inc.

 


The Miller Symposium also includes a poster session where researchers present their latest findings. Liz Lotsof and Savannah Conlon of the David Lab shared their work at the poster session, which involves DNA glycosylases NEIL1 and NEIL3 and their ability to recognize and excise oxidative damage located in G-quadruplexes.

Liz Lotsof and Savannah Conlon present their research, Recognition and excision of oxidatively damaged bases in G-quadruplexes by the DNA glycosylases NEIL1 and NEIL3 at Miller 2019. Liz is currently in her 3rd year and Savannah is in her 2nd year of the Chemistry PhD program.

 


Undergraduate Researcher Madeline Bright of the David Lab won the 2019 Francesca Miller Undergraduate Research Award for her work involving the synthesis and duplex stability analysis of previously unreported and rationally designed modified oligonucleotides developed to act as substrates for DNA repair protein MutY in enzyme assays utilized by the David Lab. The modified oligonucleotides synthesized in this project will help elucidate the target recognition mechanism of MutY. Madeline has been a member of the David Lab since January 2018 and works with 3rd year PhD student Robert Van Ostrand. Congratulations Maddy!

Maddy with Sheila after being awarded the 2019 Francesca Miller Undergraduate Research Award.

The David Lab @ Miller 2019

The David Lab brings all hands on deck to the Miller Symposium.

 

Thank you to Jackson Zhu for taking the photos.

Keywords:

#MillerSymposium #UCDavis #ChemicalBiology #DNARepair #DavidLab #SheilaDavid #UCDavisChemistry

 

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

 

 

 

 

 

We bid you adieu, Holly Vickery!

David Lab researcher Holly Vickery is off to graduate school, and the David Lab wishes her farewell. Holly worked on multiple projects as a research scientist in the David Lab. One project was focused on measuring the cellular repair efficiency of MutY variants, while another project revolved around optimizing a purification technique of MUTYH for higher yields and purity. Holly is moving on to graduate school as part of the Chemistry and Chemical Biology Program at the University of California San Francisco. We’ll miss you here at the David Lab, Holly, but we’re glad to see you move forward. Good luck at UCSF!

 

 

 

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 

 

David Lab Graduate Student Spotlight: Nicole N. Nuñez

8/28/2017

Presenting the David Lab Graduate Student Spotlight, featuring Nicole Nuñez. We discuss with Nicole how she found her way onto the STEM pathway she is currently traveling as she is completing her Ph.D, and Nicole details the powerful motivation behind her passion for investigating the mechanisms of cancer, and how her path helped lead her to the David Lab. Members of the David Lab chime in with what they like about Nicole, and how she has helped them. Additionally, Nicole gives advice for the next generation of graduate students, and as this was an interview about graduate school, the topic of pizza was eventually brought to the forefront. Nicole has been a vital member of the David Lab for some time now, and we are proud to see her moving onward. Enjoy the show!

 

Direct Link to YouTube Video:

https://youtu.be/MKDooqfjsWA

 



 

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Contact:

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

Department of Chemistry
One Shields Ave.
Davis, CA 95616