Bimodal conformations of Smc5/6 regulate molecular activities and anti-genotoxic functions
About This Grant
PROJECT SUMMARY/ABSTRACT Humans are constantly exposed to environmental genotoxins, inducing DNA lesions that lead to mutations and diseases such as cancer and developmental defects. To preserve genome integrity, cells have evolved a highly conserved network of pathways to repair DNA lesions and manage DNA replication. In eukaryotes, a key member of this network is the conserved Smc5/6 complex, which has direct roles in DNA repair and replication. Smc5/6’s functions are critical, as its dysfunction sensitizes cells to many genotoxins and devastating genome instability syndromes in humans. Despite its importance in genome maintenance, how Smc5/6 performs its anti- genotoxic functions is poorly understood. Uncovering the core principles by which Smc5/6 modulates its genomic functions is critical in understanding how cells respond to environmental genotoxins and in advancing new avenues for treating diseases. Our structural data have revealed two competing conformations of budding yeast Smc5/6 that are proposed to regulate its key activities of DNA binding and ATP hydrolysis. These conformations, termed the Nse4-neck and Nse6-neck states, are required to protect against genotoxic stress. Further, genetic tests have revealed that each conformational state is required for specific Smc5/6-mediated functions in DNA replication termination and repair intermediate removal. Thus, we hypothesize that the two Smc5/6 conformational states regulate the complex’s key biochemical activities to enable distinct genome protection roles. To test this hypothesis, this project will investigate Smc5/6’s functional mechanisms using a combination of in vitro and in vivo approaches in budding yeast. Aim 1’s experiments will examine how the two distinct conformational states of Smc5/6 regulate its biochemical activities of ATP hydrolysis and DNA binding. Aim 2 will build on preliminary genetic findings suggesting that the Nse4-neck state of Smc5/6 is recruited to stalled replication forks at rDNA sites to aid replication termination. We will test how the Smc5/6 Nse4-neck state impacts replication termination and Smc5/6 chromatin localization through genomic approaches. In Aim 3, we will expand on previous work suggesting the Nse6-neck state of Smc5/6 modulates recombinational repair factors like Sgs1 to aid in removing DNA repair intermediates. As such, we will test how perturbing the Nse6-neck state in cells affects Smc5/6-mediated repair intermediate removal and Sgs1 modulation. These Aims will reveal the mechanisms by which Smc5/6 drives its genome integrity functions to provide widespread genotoxin resistance. As Smc5/6 mutations cause genotoxin sensitivity and diseases such as genome instability syndromes, this research will guide the study of human Smc5/6 into its disease-causing mechanisms. This research plan will provide the F31 candidate strong training in the genome integrity field under the guidance of the sponsor Dr. Xiaolan Zhao, an expert in Smc5/6 biology and genome maintenance processes. Further, the candidate’s network of committed mentors and collaborators will drive their progress in mastering multidisciplinary research approaches, developing mentoring skills, and cultivating strong communication skills.
Grant Summary
Bimodal conformations of Smc5/6 regulate molecular activities and anti-genotoxic functions is a NIEHS - National Institute of Environmental Health Sciences grant providing up to $50K for university, nonprofit, healthcare org. Applications are due 2029-05-31 (open). Check eligibility and apply with FindGrants.
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Up to $50K
2029-05-31
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- 2Gather the required documents and information, including your organization details, project plan, and budget figures.
- 3Draft your application narrative and budget addressing the funder's priorities and review criteria. FindGrants can draft each section for you to review and edit.
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Bimodal conformations of Smc5/6 regulate molecular activities and anti-genotoxic functions: Frequently Asked Questions
Who is eligible for the Bimodal conformations of Smc5/6 regulate molecular activities and anti-genotoxic functions?
Bimodal conformations of Smc5/6 regulate molecular activities and anti-genotoxic functions is offered by NIEHS - National Institute of Environmental Health Sciences and is generally open to university, nonprofit, healthcare org. It is open to organizations nationwide unless the funder specifies otherwise. Review the specific eligibility terms before applying, since funders set their own requirements around organization type, location, and the population or project being served.
How much funding does the Bimodal conformations of Smc5/6 regulate molecular activities and anti-genotoxic functions provide?
Bimodal conformations of Smc5/6 regulate molecular activities and anti-genotoxic functions provides up to $50K per award from NIEHS - National Institute of Environmental Health Sciences. Actual award sizes depend on the scope of your project, available program funds, and the number of applicants, so build a budget that reflects realistic, allowable costs rather than the maximum figure.
When is the Bimodal conformations of Smc5/6 regulate molecular activities and anti-genotoxic functions deadline?
Applications for Bimodal conformations of Smc5/6 regulate molecular activities and anti-genotoxic functions are due 2029-05-31 (open). Because deadlines can change, verify the date with the funder, NIEHS - National Institute of Environmental Health Sciences, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the Bimodal conformations of Smc5/6 regulate molecular activities and anti-genotoxic functions?
To apply for Bimodal conformations of Smc5/6 regulate molecular activities and anti-genotoxic functions, confirm your eligibility, gather the required documents, and prepare a narrative and budget that address the funder's priorities. FindGrants guides you step by step and can draft each section, then exports a submission-ready application pack for this grant from NIEHS - National Institute of Environmental Health Sciences.