Scientists reveal how cells clear DNA damage faster—a key step toward better cancer drugs
Researchers have uncovered how a protein called ALC1 moves nucleosomes away from DNA breaks to speed repairs. The finding explains a critical vulnerability that cancer cells depend on, potentially opening new avenues for drugs that disrupt this repair process and make tumors more vulnerable to treatment.
Originaltitel: Asymmetric nucleosome PARylation at DNA breaks mediates directional nucleosome sliding by ALC1
<p>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.</p>