Asymmetric nucleosome PARylation at DNA breaks mediates directional nucleosome sliding by ALC1
Abstract The chromatin remodeler ALC1 is activated by DNA damage-induced poly(ADP-ribose) deposited by PARP1/PARP2 and their co-factor HPF1. ALC1 has emerged as a cancer drug target, but how it is recruited to ADP-ribosylated nucleosomes to affect their positioning near DNA breaks is unknown. Here w...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45237-8 |
| _version_ | 1797273951961874432 |
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| author | Luka Bacic Guillaume Gaullier Jugal Mohapatra Guanzhong Mao Klaus Brackmann Mikhail Panfilov Glen Liszczak Anton Sabantsev Sebastian Deindl |
| author_facet | Luka Bacic Guillaume Gaullier Jugal Mohapatra Guanzhong Mao Klaus Brackmann Mikhail Panfilov Glen Liszczak Anton Sabantsev Sebastian Deindl |
| author_sort | Luka Bacic |
| collection | DOAJ |
| description | Abstract The chromatin remodeler ALC1 is activated by DNA damage-induced poly(ADP-ribose) deposited by PARP1/PARP2 and their co-factor HPF1. ALC1 has emerged as a cancer drug target, but how it is recruited to ADP-ribosylated nucleosomes to affect their positioning near DNA breaks is unknown. Here we find that PARP1/HPF1 preferentially initiates ADP-ribosylation on the histone H2B tail closest to the DNA break. To dissect the consequences of such asymmetry, we generate nucleosomes with a defined ADP-ribosylated H2B tail on one side only. The cryo-electron microscopy structure of ALC1 bound to such an asymmetric nucleosome indicates preferential engagement on one side. Using single-molecule FRET, we demonstrate that this asymmetric recruitment gives rise to directed sliding away from the DNA linker closest to the ADP-ribosylation site. Our data suggest a mechanism by which ALC1 slides nucleosomes away from a DNA break to render it more accessible to repair factors. |
| first_indexed | 2024-03-07T14:51:28Z |
| format | Article |
| id | doaj.art-5c605abf81604ad69ac21ed529579a45 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:51:28Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-5c605abf81604ad69ac21ed529579a452024-03-05T19:39:51ZengNature PortfolioNature Communications2041-17232024-02-0115111010.1038/s41467-024-45237-8Asymmetric nucleosome PARylation at DNA breaks mediates directional nucleosome sliding by ALC1Luka Bacic0Guillaume Gaullier1Jugal Mohapatra2Guanzhong Mao3Klaus Brackmann4Mikhail Panfilov5Glen Liszczak6Anton Sabantsev7Sebastian Deindl8Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala UniversityDepartment of Cell and Molecular Biology, Science for Life Laboratory, Uppsala UniversityDepartment of Biochemistry, The University of Texas Southwestern Medical CenterDepartment of Cell and Molecular Biology, Science for Life Laboratory, Uppsala UniversityDepartment of Cell and Molecular Biology, Science for Life Laboratory, Uppsala UniversityDepartment of Cell and Molecular Biology, Science for Life Laboratory, Uppsala UniversityDepartment of Biochemistry, The University of Texas Southwestern Medical CenterDepartment of Cell and Molecular Biology, Science for Life Laboratory, Uppsala UniversityDepartment of Cell and Molecular Biology, Science for Life Laboratory, Uppsala UniversityAbstract The chromatin remodeler ALC1 is activated by DNA damage-induced poly(ADP-ribose) deposited by PARP1/PARP2 and their co-factor HPF1. ALC1 has emerged as a cancer drug target, but how it is recruited to ADP-ribosylated nucleosomes to affect their positioning near DNA breaks is unknown. Here we find that PARP1/HPF1 preferentially initiates ADP-ribosylation on the histone H2B tail closest to the DNA break. To dissect the consequences of such asymmetry, we generate nucleosomes with a defined ADP-ribosylated H2B tail on one side only. The cryo-electron microscopy structure of ALC1 bound to such an asymmetric nucleosome indicates preferential engagement on one side. Using single-molecule FRET, we demonstrate that this asymmetric recruitment gives rise to directed sliding away from the DNA linker closest to the ADP-ribosylation site. Our data suggest a mechanism by which ALC1 slides nucleosomes away from a DNA break to render it more accessible to repair factors.https://doi.org/10.1038/s41467-024-45237-8 |
| spellingShingle | Luka Bacic Guillaume Gaullier Jugal Mohapatra Guanzhong Mao Klaus Brackmann Mikhail Panfilov Glen Liszczak Anton Sabantsev Sebastian Deindl Asymmetric nucleosome PARylation at DNA breaks mediates directional nucleosome sliding by ALC1 Nature Communications |
| title | Asymmetric nucleosome PARylation at DNA breaks mediates directional nucleosome sliding by ALC1 |
| title_full | Asymmetric nucleosome PARylation at DNA breaks mediates directional nucleosome sliding by ALC1 |
| title_fullStr | Asymmetric nucleosome PARylation at DNA breaks mediates directional nucleosome sliding by ALC1 |
| title_full_unstemmed | Asymmetric nucleosome PARylation at DNA breaks mediates directional nucleosome sliding by ALC1 |
| title_short | Asymmetric nucleosome PARylation at DNA breaks mediates directional nucleosome sliding by ALC1 |
| title_sort | asymmetric nucleosome parylation at dna breaks mediates directional nucleosome sliding by alc1 |
| url | https://doi.org/10.1038/s41467-024-45237-8 |
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