Human ALC1 is an oncogene-encoded chromatin-remodeling enzyme required for DNA repair that possesses a poly(ADP-ribose) (PAR)-binding macro domain. Its engagement with PARylated PARP1 activates ALC1 at sites of DNA damage, but the underlying mechanism remains unclear. Here, we establish a dual role for the macro domain in autoinhibition of ALC1 ATPase activity and coupling to nucleosome mobilization. In the absence of DNA damage, an inactive conformation of the ATPase is maintained by juxtaposition of the macro domain against predominantly the C-terminal ATPase lobe through conserved electrostatic interactions. Mutations within this interface displace the macro domain, constitutively activate the ALC1 ATPase independent of PARylated PARP1, and alter the dynamics of ALC1 recruitment at DNA damage sites. Upon DNA damage, binding of PARylated PARP1 by the macro domain induces a conformational change that relieves autoinhibitory interactions with the ATPase motor, which selectively activates ALC1 remodeling upon recruitment to sites of DNA damage.

人类 ALC1 是一种致癌基因编码的 DNA 修复所需的染色质重塑酶，具有聚 (ADP-核糖) (PAR) 结合宏结构域。它与 PARylated PARP1 结合可激活 DNA 损伤位点的 ALC1，但其潜在机制仍不清楚。在这里，我们建立了宏结构域在 ALC1 ATP 酶活性的自动抑制和核小体动员偶联中的双重作用。在没有 DNA 损伤的情况下，通过将大结构域通过保守的静电相互作用主要与 C 端 ATP 酶叶并置，从而维持 ATP 酶的非活性构象。该界面内的突变取代了宏结构域，组成性激活独立于 PARylated PARP1 的 ALC1 ATP 酶，并改变 ALC1 在 DNA 损伤位点招募的动态。 DNA 损伤后，PARylated PARP1 与大结构域的结合会引起构象变化，从而缓解与 ATPase 马达的自抑制相互作用，从而在招募到 DNA 损伤位点时选择性激活 ALC1 重塑。