FANCD2–FANCI surveys DNA and recognizes double- to single-stranded junctions
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| Title: | FANCD2–FANCI surveys DNA and recognizes double- to single-stranded junctions |
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| Authors: | Pablo Alcón, Artur P. Kaczmarczyk, Korak Kumar Ray, Themistoklis Liolios, Guillaume Guilbaud, Tamara Sijacki, Yichao Shen, Stephen H. McLaughlin, Julian E. Sale, Puck Knipscheer, David S. Rueda, Lori A. Passmore |
| Contributors: | Hubrecht Institute with UMC, DSpace at Cambridge pro (8.1) |
| Source: | Nature |
| Publisher Information: | Springer Science and Business Media LLC, 2024. |
| Publication Year: | 2024 |
| Subject Terms: | Cell Extracts, DNA Replication, Models, Molecular, DNA Repair, DNA, Single-Stranded, Article, Diffusion, Xenopus laevis, Models, Animals, Humans, Fanconi Anemia Complementation Group D2 Protein/chemistry, General, DNA/chemistry, Fanconi Anemia Complementation Group D2 Protein, Cryoelectron Microscopy, Molecular, DNA, Fanconi Anemia Complementation Group Proteins, Single Molecule Imaging, 3. Good health, Fanconi Anemia Complementation Group Proteins/chemistry, Single-Stranded/chemistry, Female, DNA Damage, Protein Binding |
| Description: | DNA crosslinks block DNA replication and are repaired by the Fanconi anaemia pathway. The FANCD2–FANCI (D2–I) protein complex is central to this process as it initiates repair by coordinating DNA incisions around the lesion1. However, D2–I is also known to have a more general role in DNA repair and in protecting stalled replication forks from unscheduled degradation2–4. At present, it is unclear how DNA crosslinks are recognized and how D2–I functions in replication fork protection. Here, using single-molecule imaging, we show that D2–I is a sliding clamp that binds to and diffuses on double-stranded DNA. Notably, sliding D2–I stalls on encountering single-stranded–double-stranded (ss–ds) DNA junctions, structures that are generated when replication forks stall at DNA lesions5. Using cryogenic electron microscopy, we determined structures of D2–I on DNA that show that stalled D2–I makes specific interactions with the ss–dsDNA junction that are distinct from those made by sliding D2–I. Thus, D2–I surveys dsDNA and, when it reaches an ssDNA gap, it specifically clamps onto ss–dsDNA junctions. Because ss–dsDNA junctions are found at stalled replication forks, D2–I can identify sites of DNA damage. Therefore, our data provide a unified molecular mechanism that reconciles the roles of D2–I in the recognition and protection of stalled replication forks in several DNA repair pathways. |
| Document Type: | Article Other literature type |
| File Description: | application/pdf; text/xml; application/zip |
| Language: | English |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/s41586-024-07770-w |
| Access URL: | https://pubmed.ncbi.nlm.nih.gov/39085614 https://hdl.handle.net/20.500.11755/bf79e9ad-8007-4d72-9eb6-f2dcd1647d60 https://pure.knaw.nl/portal/en/publications/bf79e9ad-8007-4d72-9eb6-f2dcd1647d60 https://doi.org/10.1038/s41586-024-07770-w https://dspace.library.uu.nl/handle/1874/455837 https://www.repository.cam.ac.uk/handle/1810/373061 https://doi.org/10.1038/s41586-024-07770-w https://www.repository.cam.ac.uk/handle/1810/380380 https://doi.org/10.1038/s41586-024-07770-w |
| Rights: | CC BY |
| Accession Number: | edsair.doi.dedup.....b8be03ae13d3e171d4367bfb36b4a7e6 |
| Database: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstract: | DNA crosslinks block DNA replication and are repaired by the Fanconi anaemia pathway. The FANCD2–FANCI (D2–I) protein complex is central to this process as it initiates repair by coordinating DNA incisions around the lesion1. However, D2–I is also known to have a more general role in DNA repair and in protecting stalled replication forks from unscheduled degradation2–4. At present, it is unclear how DNA crosslinks are recognized and how D2–I functions in replication fork protection. Here, using single-molecule imaging, we show that D2–I is a sliding clamp that binds to and diffuses on double-stranded DNA. Notably, sliding D2–I stalls on encountering single-stranded–double-stranded (ss–ds) DNA junctions, structures that are generated when replication forks stall at DNA lesions5. Using cryogenic electron microscopy, we determined structures of D2–I on DNA that show that stalled D2–I makes specific interactions with the ss–dsDNA junction that are distinct from those made by sliding D2–I. Thus, D2–I surveys dsDNA and, when it reaches an ssDNA gap, it specifically clamps onto ss–dsDNA junctions. Because ss–dsDNA junctions are found at stalled replication forks, D2–I can identify sites of DNA damage. Therefore, our data provide a unified molecular mechanism that reconciles the roles of D2–I in the recognition and protection of stalled replication forks in several DNA repair pathways. |
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| ISSN: | 14764687 00280836 |
| DOI: | 10.1038/s41586-024-07770-w |