MAD2L2 dimerization and TRIP13 control shieldin activity in DNA repair
Publication date
2021-12
Authors
de Krijger, Inge
Föhr, Bastian
Pérez, Santiago Hernández
Vincendeau, Estelle
Serrat, Judit
Thouin, Alexander Marc
Susvirkar, Vivek
Lescale, Chloé
Paniagua, Inés
Hoekman, Liesbeth
Editors
Advisors
Supervisors
Document Type
Article
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Abstract
MAD2L2 (REV7) plays an important role in DNA double-strand break repair. As a member of the shieldin complex, consisting of MAD2L2, SHLD1, SHLD2 and SHLD3, it controls DNA repair pathway choice by counteracting DNA end-resection. Here we investigated the requirements for shieldin complex assembly and activity. Besides a dimerization-surface, HORMA-domain protein MAD2L2 has the extraordinary ability to wrap its C-terminus around SHLD3, likely creating a very stable complex. We show that appropriate function of MAD2L2 within shieldin requires its dimerization, mediated by SHLD2 and accelerating MAD2L2-SHLD3 interaction. Dimerization-defective MAD2L2 impairs shieldin assembly and fails to promote NHEJ. Moreover, MAD2L2 dimerization, along with the presence of SHLD3, allows shieldin to interact with the TRIP13 ATPase, known to drive topological switches in HORMA-domain proteins. We find that appropriate levels of TRIP13 are important for proper shieldin (dis)assembly and activity in DNA repair. Together our data provide important insights in the dependencies for shieldin activity.
Keywords
General Chemistry, General Biochemistry,Genetics and Molecular Biology, General Physics and Astronomy
Citation
de Krijger, I, Föhr, B, Pérez, S H, Vincendeau, E, Serrat, J, Thouin, A M, Susvirkar, V, Lescale, C, Paniagua, I, Hoekman, L, Kaur, S, Altelaar, M, Deriano, L, Faesen, A C & Jacobs, J J L 2021, 'MAD2L2 dimerization and TRIP13 control shieldin activity in DNA repair', Nature Communications, vol. 12, no. 1, 5421. https://doi.org/10.1038/s41467-021-25724-y