Kaur Upneet, Wu Hao, Cheng Yifan, Narlikar Geeta J
Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA.
Biophysics Graduate Program, University of California San Francisco, San Francisco, CA, USA.
Science. 2025 Jul 17;389(6757):eadr3831. doi: 10.1126/science.adr3831.
Increasing the flanking DNA from 40 to 80 base pairs (bp) causes ~100-fold faster nucleosome sliding by INO80. A prevalent hypothesis posits that the Arp8 module within INO80 enables a ruler-like activity. Using cryogenic electron microscopy, we show that on nucleosomes with 40 bp of flanking DNA, the Arp8 module rotates 180° away from the DNA. Deleting the Arp8 module enables rapid sliding irrespective of flanking DNA length. Thus, rather than enabling a ruler-like activity, the Arp8 module acts as a brake on INO80 remodeling when flanking DNA is short. This autoinhibition-based mechanism has broad implications for understanding how primitive nucleosome mobilization enzymes may have evolved into sophisticated remodelers.
将侧翼DNA从40个碱基对（bp）增加到80个碱基对会使INO80介导的核小体滑动速度加快约100倍。一个普遍的假说是，INO80中的Arp8模块具有类似尺子的活性。通过低温电子显微镜，我们发现，在侧翼DNA为40 bp的核小体上，Arp8模块会旋转180°远离DNA。删除Arp8模块后，无论侧翼DNA长度如何，都能实现快速滑动。因此，Arp8模块并非具有类似尺子的活性，而是在侧翼DNA较短时，对INO80重塑起到制动作用。这种基于自抑制的机制对于理解原始核小体动员酶如何进化为复杂的重塑酶具有广泛的意义。
