Asymmetric nucleosome PARylation at DNA breaks mediates directional nucleosome sliding by ALC1.
Asymmetric nucleosome PARylation at DNA breaks mediates directional nucleosome sliding by ALC1.
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DOI：
10.1038/s41467-024-45237-8
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发表时间：
2024-02-02
影响因子：
16.6
通讯作者：
Deindl, Sebastian
中科院分区：
文献类型：
--
作者：
Bacic, Luka;Gaullier, Guillaume;Mohapatra, Jugal;Mao, Guanzhong;Brackmann, Klaus;Panfilov, Mikhail;Liszczak, Glen;Sabantsev, Anton;Deindl, Sebastian
染色质重塑蛋白ALC 1被PARP 1/PARP 2及其辅因子HPF 1沉积的DNA损伤诱导的聚（ADP-核糖）激活。ALC 1已成为癌症药物的靶点，但它如何被招募到ADP-核糖基化的核小体中以影响它们在DNA断裂附近的定位尚不清楚。在这里，我们发现PARP 1/HPF 1优先启动ADP-核糖基化的组蛋白H2 B尾部最接近的DNA断裂。为了剖析这种不对称性的后果，我们生成了仅在一侧具有确定的ADP-核糖基化H2 B尾的核小体。与这种不对称核小体结合的ALC 1的冷冻电子显微镜结构表明一侧优先接合。使用单分子FRET，我们证明，这种不对称的招聘引起的指导滑动远离最接近的ADP-核糖基化位点的DNA接头。我们的数据表明了一种机制，通过这种机制，ALC 1将核小体从DNA断裂处滑开，使其更容易被修复因子修复。Bacic等人证明PARP 1/HPF 1优先修饰最接近DNA断裂的组蛋白尾部，指导ALC 1催化的核小体滑动。这些发现表明了一种使DNA断裂更容易被修复因子修复的机制。
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. Bacic et al. demonstrate that PARP1/HPF1 preferentially modify histone tails closest to the DNA break, directing ALC1-catalyzed nucleosome sliding. These findings suggest a mechanism for rendering DNA breaks more accessible to repair factors.
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影响因子：
16
作者：
Gibbs-Seymour I;Fontana P;Rack JGM;Ahel I
通讯作者：
Ahel I
影响因子：
14.9
作者：
Chittori, Sagar;Hong, Jingjun;Subramaniam, Sriram
通讯作者：
Subramaniam, Sriram
影响因子：
15
作者：
Dao HT;Liu H;Mashtalir N;Kadoch C;Muir TW
通讯作者：
Muir TW
影响因子：
14.9
作者：
El-Khamisy, SF;Masutani, M;Caldecott, KW
通讯作者：
Caldecott, KW
DOI：
10.1107/s2059798318006551
发表时间：
2018-06-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Poon BK;Read RJ;Sobolev OV;Terwilliger TC;Urzhumtsev A;Adams PD
通讯作者：
Adams PD