The strand exchange domain of tumor suppressor PALB2 is intrinsically disordered and promotes oligomerization-dependent DNA compaction
Summary: The partner and localizer of BRCA2 (PALB2) is a scaffold protein linking BRCA1 with BRCA2 and RAD51 during homologous recombination (HR). PALB2 interaction with DNA strongly enhances HR in cells, while the PALB2 DNA-binding domain (PALB2-DBD) supports DNA strand exchange in vitro. We determ...
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Elsevier
2024-12-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224024842 |
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| author | Yevhenii Kyriukha Maxwell B. Watkins Jennifer M. Redington Nithya Chintalapati Abhishek Ganti Reza Dastvan Vladimir N. Uversky Jesse B. Hopkins Nicola Pozzi Sergey Korolev |
| author_facet | Yevhenii Kyriukha Maxwell B. Watkins Jennifer M. Redington Nithya Chintalapati Abhishek Ganti Reza Dastvan Vladimir N. Uversky Jesse B. Hopkins Nicola Pozzi Sergey Korolev |
| author_sort | Yevhenii Kyriukha |
| collection | DOAJ |
| description | Summary: The partner and localizer of BRCA2 (PALB2) is a scaffold protein linking BRCA1 with BRCA2 and RAD51 during homologous recombination (HR). PALB2 interaction with DNA strongly enhances HR in cells, while the PALB2 DNA-binding domain (PALB2-DBD) supports DNA strand exchange in vitro. We determined that PALB2-DBD is intrinsically disordered beyond a single N-terminal α-helix. Coiled-coil mediated dimerization is stabilized by interaction between intrinsically disordered regions (IDRs) leading to a 2-fold structural compaction. Single-stranded (ss)DNA binding promotes additional structural compaction and protein tetramerization. Using confocal single-molecule FRET, we observed bimodal and oligomerization-dependent compaction of ssDNA bound to PALB2-DBD, suggesting a novel strand exchange mechanism. Bioinformatics analysis and preliminary observations indicate that PALB2 forms protein-nucleic acids condensates. Intrinsically disordered DBDs are prevalent in the human proteome. PALB2-DBD and similar IDRs may use a chaperone-like mechanism to aid formation and resolution of DNA and RNA multichain intermediates during DNA replication, repair and recombination. |
| format | Article |
| id | doaj-art-c439c487940a4e6fa6c652461f0b310b |
| institution | OA Journals |
| issn | 2589-0042 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-c439c487940a4e6fa6c652461f0b310b2025-08-20T01:57:08ZengElsevieriScience2589-00422024-12-01271211125910.1016/j.isci.2024.111259The strand exchange domain of tumor suppressor PALB2 is intrinsically disordered and promotes oligomerization-dependent DNA compactionYevhenii Kyriukha0Maxwell B. Watkins1Jennifer M. Redington2Nithya Chintalapati3Abhishek Ganti4Reza Dastvan5Vladimir N. Uversky6Jesse B. Hopkins7Nicola Pozzi8Sergey Korolev9Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St Louis, MO, USAThe Biophysics Collaborative Access Team (BioCat), Departments of Biology and Physics, Illinois Institute of Technology, Chicago, IL, USAEdward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St Louis, MO, USAEdward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St Louis, MO, USAEdward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St Louis, MO, USAEdward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St Louis, MO, USADepartment of Molecular Medicine and USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USAThe Biophysics Collaborative Access Team (BioCat), Departments of Biology and Physics, Illinois Institute of Technology, Chicago, IL, USAEdward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St Louis, MO, USAEdward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St Louis, MO, USA; Corresponding authorSummary: The partner and localizer of BRCA2 (PALB2) is a scaffold protein linking BRCA1 with BRCA2 and RAD51 during homologous recombination (HR). PALB2 interaction with DNA strongly enhances HR in cells, while the PALB2 DNA-binding domain (PALB2-DBD) supports DNA strand exchange in vitro. We determined that PALB2-DBD is intrinsically disordered beyond a single N-terminal α-helix. Coiled-coil mediated dimerization is stabilized by interaction between intrinsically disordered regions (IDRs) leading to a 2-fold structural compaction. Single-stranded (ss)DNA binding promotes additional structural compaction and protein tetramerization. Using confocal single-molecule FRET, we observed bimodal and oligomerization-dependent compaction of ssDNA bound to PALB2-DBD, suggesting a novel strand exchange mechanism. Bioinformatics analysis and preliminary observations indicate that PALB2 forms protein-nucleic acids condensates. Intrinsically disordered DBDs are prevalent in the human proteome. PALB2-DBD and similar IDRs may use a chaperone-like mechanism to aid formation and resolution of DNA and RNA multichain intermediates during DNA replication, repair and recombination.http://www.sciencedirect.com/science/article/pii/S2589004224024842BiochemistryMolecular biologyCell biology |
| spellingShingle | Yevhenii Kyriukha Maxwell B. Watkins Jennifer M. Redington Nithya Chintalapati Abhishek Ganti Reza Dastvan Vladimir N. Uversky Jesse B. Hopkins Nicola Pozzi Sergey Korolev The strand exchange domain of tumor suppressor PALB2 is intrinsically disordered and promotes oligomerization-dependent DNA compaction iScience Biochemistry Molecular biology Cell biology |
| title | The strand exchange domain of tumor suppressor PALB2 is intrinsically disordered and promotes oligomerization-dependent DNA compaction |
| title_full | The strand exchange domain of tumor suppressor PALB2 is intrinsically disordered and promotes oligomerization-dependent DNA compaction |
| title_fullStr | The strand exchange domain of tumor suppressor PALB2 is intrinsically disordered and promotes oligomerization-dependent DNA compaction |
| title_full_unstemmed | The strand exchange domain of tumor suppressor PALB2 is intrinsically disordered and promotes oligomerization-dependent DNA compaction |
| title_short | The strand exchange domain of tumor suppressor PALB2 is intrinsically disordered and promotes oligomerization-dependent DNA compaction |
| title_sort | strand exchange domain of tumor suppressor palb2 is intrinsically disordered and promotes oligomerization dependent dna compaction |
| topic | Biochemistry Molecular biology Cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224024842 |
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