Asymmetric nucleosome PARylation at DNA breaks mediates directional nucleosome sliding by ALC1.
Luka BacicGuillaume GaullierJugal MohapatraGuanzhong MaoKlaus BrackmannMikhail PanfilovGlen LiszczakAnton SabantsevSebastian DeindlPublished in: Nature communications (2024)
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.
Keyphrases
- single molecule
- dna damage
- dna repair
- electron microscopy
- circulating tumor
- living cells
- atomic force microscopy
- cell free
- oxidative stress
- gene expression
- diabetic rats
- squamous cell carcinoma
- machine learning
- solid state
- high glucose
- emergency department
- transcription factor
- big data
- mass spectrometry
- social media
- circulating tumor cells
- data analysis
- lymph node metastasis