Emerging Researchers National (ERN) Conference

nsf-logo[1]

  • About
    • About AAAS
    • About the NSF
    • About the Conference
    • Partners/Supporters
    • Project Team
  • Registration
    • Conference Registration
    • Exhibitor Registration
    • Hotel Reservations
  • Abstracts
    • Abstract Submission Process
    • Presentation Schedules
    • Abstract Submission Guidelines
    • Presentation Guidelines
    • Undergraduate Abstract Locator (2020)
    • Graduate Abstract Locator (2020)
    • Faculty Abstract Locator (2020)
  • Travel Awards
  • Resources
    • App
    • Award Winners
    • Code of Conduct-AAAS Meetings
    • Code of Conduct-ERN Conference
    • Conference Agenda
    • Conference Materials
    • Conference Program Books
    • ERN Photo Galleries
    • Events | Opportunities
    • Exhibitor Info
    • HBCU-UP/CREST PI/PD Meeting
    • In the News
    • NSF Harassment Policy
    • Plenary Session Videos
    • Professional Development
    • Science Careers Handbook
    • Additional Resources
    • Archives
  • Engage
    • Webinars
    • Video Contest
    • Video Contest Winners
    • ERN 10-Year Anniversary Videos
    • Plenary Session Videos
  • Contact Us
  • App View

Interactions Between the MSH2-MSH6 and MLH1-PMS2 Mismatch Repair Protein Complexes on Mismatched DNA

Graduate #1
Discipline: Biological Sciences
Subcategory: Biochemistry (not Cell and Molecular Biology and Genetics)

Nilse Lene Dos Santos - University of Connecticut Health (UConn Health)
Co-Author(s): Dipika Gupta and Christopher D. Heinen, UConn Health, Farmington, CT



Lynch syndrome (LS), a colorectal cancer predisposition syndrome, is the most common form of hereditary colon cancer. Caused by the inheritance of mutations in mismatch repair (MMR) genes, LS results in an increased lifetime risk of developing colonic and extra-colonic cancers. These cancers are often at an early age. MMR maintains genomic stability by recognizing and coordinating the repair of single base-pair mismatches and insertion/deletion loops resulting from replication errors. MMR deficiency enables fixation of mutations that eventually lead to cancer development. MMR is composed of four main genes: MSH2, MSH6, MLH1 and PMS2. The MSH2 and MSH6 proteins form a heterodimer that recognizes mismatches on DNA and recruits a heterodimer of MLH1 and PMS2. Together, they signal the recruitment of Exonuclease I to remove the erroneous region on the daughter strand. Previous studies have indicated that MSH2-MSH6 bound to ATP forms a sliding clamp on the DNA that is required for its interaction with MLH1-PMS2. However, the nature and stoichiometry of this interaction remains elusive. Current models propose that MSH2- MSH6 and MLH1-PMS2 form a quaternary structure on DNA and function as a unit to promote repair, but there is no direct evidence for this structure. We therefore explored the hypothesis that the two heterodimers form stable quaternary structures that function as a unit on mismatch containing DNA. Using an in vitro system with biotinylated mismatch-containing DNA and streptavidin coated magnetic beads, we were able to isolate both MSH2 and MLH1 MMR protein-DNA complexes to study their interaction and stability. As a control, we examined the binding of MLH1 to mismatched DNA in the absence of ATP or MSH2-MSH6. We found that MLH1-PMS2 required MSH2- MSH6 for initial recruitment to mismatch-containing DNA, however, MLH1-PMS2 remained stable on DNA even after MSH2-MSH6 had dissociated. These results suggest that MSH2- MSH6 loads MLH1-PMS2 onto mismatch-containing DNA and that a stable, quaternary unit is not necessarily required. Future experiments will be necessary to examine stoichiometry of the two MMR heterodimers on DNA as well as confirm whether MLH1-PMS2 is directly binding to DNA and has functional roles that are independent of MSH2-MSH6 binding. These studies will improve our knowledge of the mechanism by which MMR maintains genomic stability. Ultimately, this understanding can be used to improve prevention and treatment MMR-defective cancers.

Not Submitted

Funder Acknowledgement(s): Young Innovative Investigator Program at Connecticut Institute Center for Clinical and Translational Science, UConn Health

Faculty Advisor: Christopher Heinen, cheinen@uchc.edu

ERN Conference

Celebrating 10 years of ERN!

What’s New

  • Webinars
  • Events|Opportunities
  • AAAS CEO Comments on Social Unrest, Racism, and Inequality
  • Maintaining Accessibility in Online Teaching During COVID-19
  • In the News
  • #ShutDownSTEM
  • HBCU/CREST PI/PD Meeting

Conference Photos

ERN Conference Photo Galleries

Awards

ERN Conference Award Winners

Checking In

Navigation

  • About the ERN Conference
  • Partners/Supporters
  • Abstracts
  • Travel Awards
  • Conference Registration
  • Exhibitor Registration
  • Hotel Reservations

nsf-logo[1]

This material is based upon work supported by the National Science Foundation (NSF) under Grant No. DUE-1930047. Any opinions, findings, interpretations, conclusions or recommendations expressed in this material are those of its authors and do not represent the views of the AAAS Board of Directors, the Council of AAAS, AAAS’ membership or the National Science Foundation.

AAAS

1200 New York Ave, NW Washington,DC 20005
202-326-6400
Contact Us
About Us

The World's Largest General Scientific Society

Useful Links

  • Membership
  • Careers at AAAS
  • Privacy Policy
  • Terms of Use

Focus Areas

  • Science Education
  • Science Diplomacy
  • Public Engagement
  • Careers in STEM

 

  • Shaping Science Policy
  • Advocacy for Evidence
  • R&D Budget Analysis
  • Human Rights, Ethics & Law
© 2021 American Association for the Advancement of Science