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January 5, 2024
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Delving into polymerase alpha-primase dynamics
In eukaryotes, DNA replication relies on the synthesis of a chimeric RNA/DNA primer by the heterotetrameric polymerase alpha-primase (pol-prim) enzyme. The primers generated by pol-prim consist of 7-10 ribonucleotides followed by ~20 deoxyribonucleotides and are generated by distinct active sites in the primase and polymerase subunits. Both primase and polymerase alpha consist of a catalytic and a regulatory subunit: PRIM1 and PRIM2 for primase and POLA1 and POLA2 for polymerase alpha. PRIM2 is further divided into PRIM2N, which acts as a scaffold between primase and pol alpha subunits, and PRIM2C, which regulates both DNA and RNA synthesis. While the necessity of PRIM2C for RNA primer synthesis has been well established biochemically, a direct structural characterization of the priming complex during RNA catalysis has not been conducted.
In this recent study, Johnny Cordoba, recent Chazin lab graduate, and Elwood Mullins, a research assistant professor in the Eichman lab, et al. used a combination of structural and biophysical techniques to investigate the role of PRIM2C in primer synthesis. Small-angle X-ray scattering (SAXS) and negative stain EM demonstrated that significant interdomain flexibility exists within the entire pol-prim heterotetramer and PRIM2C especially adopts a wide range of orientations relative to the tetramer core. Microscale thermophoresis also determined that PRIM1, the catalytic domain, did not bind substrate with any appreciable affinity.
 Taken together, these data suggest a model in which PRIM2C acts as both a processivity factor and length regulator in RNA synthesis. Firstly, tight binding between PRIM2C and the substrate along with inter-domain flexibility of pol-prim allows for PRIM1 association and disassociation during distributive synthesis of the RNA primer. Secondly, the ready dissociation of PRIM1 from its substrate and higher affinity of the POLA1 catalytic domain for full-length RNA-primed template facilitate handoff of the template from primase to polymerase alpha at specific lengths of 7-10 ribonucleotides. This model sheds new light on the intricacies of RNA primer synthesis and provides framework for future studies into the interplay of components in the replisome.
Read more about pol-prim dynamics here!
 MBTP/CSB Seminar Series
Allison Walker, Chemistry and Biological Sciences
Machine learning strategies for natural product discovery and biosynthesis
January 9, 12:20pm, 1220 MRB3
Add this to your calendar
 CryoEM Quarterly User Meeting
January 9, 1pm, 5131 MRB3 and via Zoom
Zoom link listed in calendar invite
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Other Seminars & Events
ASPIRE Job Search Series for PhD Students and Postdocs
Kim Petrie, BRET Office of Career Development
Resumes/Industry CVs
January 11, 11am, 411 LH
More information
Vanderbilt Postdoctoral Association Speak Easy
A Postdoc Talk Series to Tell Your Scientific “Story”
January 18, 5pm, Alumni Hall Lounge
More information and RSVP
Frontiers in Biochemistry Seminar Series
Kerney Jebrell Glover, Lehigh University
Membrane protein hairpins: Insights into the structure and topology of caveolin and oleosin
January 19, 12pm, 214 LH
Add this to your calendar
CSB Monthly Gathering
Hosted by the Yang and Ren Labs
An informal meeting with food and drink provided
January 19, 4:30-6pm, 5th floor atrium, MRB3
Add this to your calendar
ASPIRE Cafe for Postdoctoral Fellows
Ashley Brady, BRET Office of Career Development
Orientation to ASPIRE Resources for Postdocs
January 25, 11am, 411 LH
More information
Frontiers in Biochemistry Seminar Series
Yi Ren, Vanderbilt University
Mechanisms and viral inhibition of mRNA nuclear export
February 2, 12pm, 214 LH
Followed by meet-and-greet luncheon in 618 LH
Add this to your calendar
ASPIRE Biomedical Scientist’s Toolkit
Kathy Gould, BRET Office of Career Development
Preparing to Mentor
March 21, 11am, 411 LH
More information
CSB Symposium 2024
Nozomi Ando, Cornell University
James Fraser, UCSF
Jeanne Hardy, UMass Amherst
Andrej Sali, UCSF
March 28, 2024
Student Life Center, Vanderbilt University
More information
Register here
VI4 Seminar Series
Steven Damo, Fisk University
March 19, 10:30am, 512LH
Co-sponsored by the CSB
2024 VIRAL International Symposium: Research and Stories
April 18
Register here
VI4 Seminar 7th Annual Research Symposium
April 19, 8:30am-6pm, Student Life Center
Register here
Southeastern Microscopy Society Annual Meeting
May 8–10, 2024
Chattanooga, TN
More information
VI4 Seminar Series
Erica Ollman Saphire, La Jolla Institute for Immunology
October 8, 2024
Co-sponsored by the CSB
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Announcements
Register for CSB Symposium 2024
Register now for CSB Symposium 2024! Join us for an exciting day of research, collaboration and networking on Thursday, March 28, on the Vanderbilt campus.
The event will be held in the Student Life Center and will feature scientific talks from Nozomi Ando, James Fraser, Jeanne Hardy and Andrej Sali. The program also includes scientific talks from CSB junior faculty, a poster flash and poster session, a reception and Science Jeopardy, led by the incomparable Ray Blind!
Visit the CSB Symposium 2024 website for more information and program updates.
Register here. The deadline to submit an abstract for the poster session is March 1.
CryoSPARC Q&A – January 17
The CSB CryoEM facility directors are hosting a CryoSPARC Q&A on Wednesday, January 17, 1pm-5pm. The Q&A session will be held in 5139 MRB3 (CSB Library) and via Teams.
The meeting will give those who have already worked with the CryoSPARC software an opportunity to ask specific questions and discuss higher-level processing topics. While drop-in questions are welcome, submitting topics in advance will help the team organize the session. Please send questions and topics to Melissa Chambers by January 10.
2024 VIRAL Research Symposium
Registration is open for the VIRAL International Symposium: Research and Stories hosted by the Vanderbilt International Researchers Alliance (VIRAL). The event, scheduled for April 18, is open to the entire Vanderbilt community. The registration deadline is April 1 with abstract submissions due by February 20.
For more information, email VIRAL.
Register here.
Did you know that the Vanderbilt Office of Postdoctoral Affairs has a new Slack channel for VU and VUMC postdocs?
It includes dedicated channels for general announcements, calendar events and more.
Sign in using your VU or VUMC email address at vandypostdocs.slack.com. This is a brand new channel so please “re-sign up” if you used the previous channel.
Eli McDonald, Meiler & Plate Labs
January 23 – Karpay Award Presentation
CFTR Folding: Started from the Translocon Now We Here
Jessica Taylor, Brown Lab, and Breann Brown, Biochemistry
January 30 – RCR Special Session
Our Obligation to Society as Scientists, If We Have One
Lauren Buchanan, Chemistry
February 6
 Follow us on X (formerly Twitter): @VanderbiltCSB
 Join the CSB & MBTP Group on LinkedIn!
Do you have a structure, seminar or other announcement to share with the CSB/MBTP community? Did you or another lab member just complete a marathon or other mind-boggling feat?
Whatever you want to announce, email Karen Davis and tell her about it! She’ll include it in Weekly Coordinates!
 Communications Team: Borden Lacy, Karen Davis and Cameron Cohen
Wanna join the team? Email Karen for more information.
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CSB Publications for December 2023
- 3D reconstruction of murine mitochondria reveals changes in structure during aging linked to the MICOS complex. Vue Z, Garza-Lopez E, Neikirk K, Katti P, Vang L, Beasley H, Shao J, Marshall AG, Crabtree A, Murphy AC, Jenkins BC, Prasad P, Evans C, Taylor B, Mungai M, Killion M, Stephens D, Christensen TA, Lam J, Rodriguez B, Phillips MA, Daneshgar N, Koh HJ, Koh A, Davis J, Devine N, Saleem M, Scudese E, Arnold KR, Vanessa Chavarin V, Daniel Robinson R, Chakraborty M, Gaddy JA, Sweetwyne MT, Wilson G, Zaganjor E, Kezos J, Dondi C, Reddy AK, Glancy B, Kirabo A, Quintana AM, Dai DF, Ocorr K, Murray SA, Damo SM, Exil V, Riggs B, Mobley BC, Gomez JA, McReynolds MR, Hinton A Jr. Aging Cell. 2023 Dec;22(12):e14009. doi: 10.1111/acel.14009. Epub 2023 Nov 13. PMID: 37960952 Free PMC article.
- Time-resolved live-cell spectroscopy reveals EphA2 multimeric assembly. Shi X, Lingerak R, Herting CJ, Ge Y, Kim S, Toth P, Wang W, Brown BP, Meiler J, Sossey-Alaoui K, Buck M, Himanen J, Hambardzumyan D, Nikolov DB, Smith AW, Wang B. Science. 2023 Dec;382(6674):1042-1050. doi: 10.1126/science.adg5314. Epub 2023 Nov 16. PMID: 37972196
- A pilot study on our non-traditional, varied writing accountability group for historically excluded and underrepresented persons in STEMM. Neikirk K, Barongan T, Shao B, Spencer EC, Kabugi K, Conley Z, Vang L, Vue M, Vang N, Garza-Lopez E, Crabtree A, Alexander S, Beasley HK, Marshall AG, Killion M, Stephens D, Owens B, Martinez D, Palavicino-Maggio CB, Jenkins F, Vang C, Morton DJ, Shuler H, Murray SA, Damo S, Vue Z, Hinton A Jr. Heliyon. 2023 Nov 22;9(12):e22335. doi: 10.1016/j.heliyon.2023.e22335. eCollection 2023 Dec. PMID: 38144282 Free PMC article.
- Go big and go home: A bulky extension makes promiscuous ligands settle down. Yu X, Kojetin DJ. Structure. 2023 Dec 7;31(12):1520-1522. doi: 10.1016/j.str.2023.11.001. PMID: 38065074
- Environmental Toxicant Exposure Paralyzes Human Placental Macrophage Responses to Microbial Threat. Stephens VR, Moore RE, Spicer SK, Talbert JA, Lu J, Chinni R, Chambers SA, Townsend SD, Manning SD, Rogers LM, Aronoff DM, Vue Z, Neikirk K, Hinton AO Jr, Damo SM, Noble KN, Eastman AJ, McCallister MM, Osteen KG, Gaddy JA. ACS Infect Dis. 2023 Dec 8;9(12):2401-2408. doi: 10.1021/acsinfecdis.3c00490. Epub 2023 Nov 13. PMID: 37955242
- A Fluorescence-Based Sensor for Calibrated Measurement of Protein Kinase Stability in Live Cells. Paul JW 3rd, Muratcioğlu S, Kuriyan J. bioRxiv. 2023 Dec 8:2023.12.07.570636. doi: 10.1101/2023.12.07.570636. Preprint. PMID: 38106090 Free PMC article.
- Is space the final frontier for mitochondrial study? Neikirk K, Stephens DC, Beasley HK, Marshall AG, Gaddy JA, Damo SM, Hinton A Jr. Biotechniques. 2023 Dec 12. doi: 10.2144/btn-2023-0071. Online ahead of print. PMID: 38084381 Free article.
- Development of LIBRA-seq for the guinea pig model system as a tool for the evaluation of antibody responses to multivalent HIV-1 vaccines. Vukovich MJ, Raju N, Kgagudi P, Manamela NP, Abu-Shmais AA, Gripenstraw KR, Wasdin PT, Shen X, Dwyer B, Akoad J, Lynch RM, Montefiori DC, Richardson SI, Moore PL, Georgiev IS. J Virol. 2023 Dec 12:e0147823. doi: 10.1128/jvi.01478-23. Online ahead of print. PMID: 38085509
- TCR signaling promotes formation of an STS1-Cbl-b complex with pH-sensitive phosphatase activity that suppresses T cell function in acidic environments. Tsai YL, Arias-Badia M, Kadlecek TA, Lwin YM, Srinath A, Shah NH, Wang ZE, Barber D, Kuriyan J, Fong L, Weiss A. Immunity. 2023 Dec 12;56(12):2682-2698.e9. doi: 10.1016/j.immuni.2023.11.010. PMID: 38091950
- Identification of Structural Motifs Critical for Human G6PC2 FunctionInformed by Sequence Analysis and an AlphaFold2-Predicted Model. O’Brien RM, Hawes EM, Claxton DP, Oeser JK. Biosci Rep. 2023 Dec 14:BSR20231851. doi: 10.1042/BSR20231851. Online ahead of print. PMID: 38095063 Free article.
- Flexibility and Distributive Synthesis Regulate RNA Priming and Handoff in Human DNA Polymerase α-Primase. Cordoba JJ, Mullins EA, Salay LE, Eichman BF, Chazin WJ. J Mol Biol. 2023 Dec 15;435(24):168330. doi: 10.1016/j.jmb.2023.168330. Epub 2023 Oct 24. PMID: 37884206
- Base-Displaced Intercalated Structure of the 3-(2-Deoxy-β-D-erythropentofuranosyl)-pyrimido[1,2-f]purine-6,10(3H,5H)-dione (6-oxo-M1dG) Lesion in DNA. Fu Y, Christov PP, Kingsley PJ, Richie-Jannetta RM, Marnett LJ, Stone MP. Chem Res Toxicol. 2023 Dec 18;36(12):1947-1960. doi: 10.1021/acs.chemrestox.3c00226. Epub 2023 Nov 21. PMID: 37989274 Free PMC article.
- Substrate Positioning Dynamics Involves a Non-Electrostatic Component to Mediate Catalysis. Jiang Y, Ding N, Shao Q, Stull SL, Cheng Z, Yang ZJ. J Phys Chem Lett. 2023 Dec 21;14(50):11480-11489. doi: 10.1021/acs.jpclett.3c02444. Epub 2023 Dec 12. PMID: 38085952
- Structure-Based Discovery of Potent, Orally Bioavailable Benzoxazepinone-Based WD Repeat Domain 5 Inhibitors. Teuscher KB, Mills JJ, Tian J, Han C, Meyers KM, Sai J, South TM, Crow MM, Van Meveren M, Sensintaffar JL, Zhao B, Amporndanai K, Moore WJ, Stott GM, Tansey WP, Lee T, Fesik SW. J Med Chem. 2023 Dec 28;66(24):16783-16806. doi: 10.1021/acs.jmedchem.3c01529. Epub 2023 Dec 12. PMID: 38085679
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