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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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-12-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224024842 |
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| Summary: | 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. |
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| ISSN: | 2589-0042 |