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PreprintCited by 3Protein Structure and DynamicsDNA Repair MechanismsDNA and Nucleic Acid Chemistry

The strand exchange domain of tumor suppressor PALB2 is intrinsically disordered and promotes oligomerization-dependent DNA compaction.

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Kyriukha, Yevhenii, Watkins, Maxwell B, Redington, Jennifer M, Dastvan, Reza, Uversky, Vladimir N, Hopkins, Jesse B, Pozzi, Nicola, Korolev, Sergey·2023·iScience
DOI 10.1101/2023.06.01.543259PMC PMC11582789

Preprint — published as 10.1016/j.isci.2024.111259

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Abstract

The Partner and Localizer of BRCA2 (PALB2) is a scaffold protein that links BRCA1 with BRCA2 to initiate homologous recombination (HR). PALB2 interaction with DNA strongly enhances HR efficiency in cells. The PALB2 DNA-binding domain (PALB2-DBD) supports strand exchange, a complex multistep reaction conducted by only a few proteins such as RecA-like recombinases and Rad52. Using bioinformatics analysis, small-angle X-ray scattering, circular dichroism, and electron paramagnetic spectroscopy, we determined that PALB2-DBD is an intrinsically disordered region (IDR) forming compact molten globule-like dimer. IDRs contribute to oligomerization synergistically with the coiled-coil interaction. Using confocal single-molecule FRET we demonstrated that PALB2-DBD compacts single-stranded DNA even in the absence of DNA secondary structures. The compaction is bimodal, oligomerization-dependent, and is driven by IDRs, suggesting a novel strand exchange mechanism. Intrinsically disordered proteins (IDPs) are prevalent in the human proteome. Novel DNA binding properties of PALB2-DBD and the complexity of strand exchange mechanism significantly expands the functional repertoire of IDPs. Multivalent interactions and bioinformatics analysis suggest that PALB2 function is likely to depend on formation of protein-nucleic acids condensates. Similar intrinsically disordered DBDs may use chaperone-like mechanism to aid formation and resolution of DNA and RNA multichain intermediates during DNA replication, repair and recombination.

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Authors
Kyriukha, Y., Watkins, M. B., Redington, J. M., Dastvan, R., Uversky, V. N., Hopkins, J. B., Pozzi, N., & Korolev, S.
Affiliations
  • Saint Louis University (US)
  • Illinois Institute of Technology (US)
  • University of South Florida (US)
Corresponding author
Korolev, Sergey
ORCID
Venue
iScience
Publisher
openRxiv
Published
2023-06-02
Volume
27
Issue
12
Pages
111259-111259
ISSN
2589-0042 (ISSN-L)
DOI
10.1101/2023.06.01.543259
PMC
PMC11582789
OpenAlex
W4403902487
Cited by
3
References
1
Citations by year
2026: 1 · 2025: 2
FWCI
0.41
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • iScience (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Science Foundation (1829070, DE-AC02–06CH11357, 1-P30-GM124166-01A1)
  • U.S. Department of Energy (DE‐ AC02‐06CH11357, DMR-1829070, AC02‐06CH11357, 06CH11357, P30 GM138395, DE-AC02-)
  • Empire State Development Corporation
  • Institute of Clinical and Translational Sciences (TR002345, UL1 TR002345)
  • Saint Louis University
  • Swine Innovation Porc
  • Alvin J. Siteman Cancer Center
  • National Institutes of Health (1s10od030343-01, DE-AC02–06CH11357, GM124166, UL1TR002345)
  • Office of Science (AC02‐06CH11357, DE-AC02, 06CH11357, DE-AC02-06CH11357)
  • Stephenson Cancer Center
  • National Cancer Institute (R37CA265877)
  • National Institute of General Medical Sciences (GM138395, S10 OD030343, 1-P30-GM124166, 1‐P30‐GM124166‐01A1, DE-AC02-06CH11357, GM‐124166, DMR-1829070, R01GM073837, P30GM138395, R01GM154323, P30GM124166)
  • Division of Materials Research (DE-AC02-06CH11357, DMR-1829070, 1829070)
  • National Center for Advancing Translational Sciences
  • Argonne National Laboratory (DE- AC02-06-CH11357, DE-AC02, AC02–06CH11357, 06CH11357, P30 GM138395)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
Keywords
PALB2, intrinsically disordered regions, DNA strand exchange, DNA-binding domain, coiled-coil dimerization, protein oligomerization, DNA condensation, single-stranded DNA binding, homologous recombination, BRCA2, single-molecule FRET

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