Polycomb repressive complex 1 (PRC1) modifies chromatin through catalysis of histone H2A lysine 119 monoubiquitination (H2AK119ub1). RING1 and RNF2 interchangeably serve as the catalytic subunit within PRC1. Pathogenic missense variants in PRC1 core components reveal functions of these proteins that are obscured in knockout models. While Ring1a knockout models remain healthy, the microcephaly and neuropsychiatric phenotypes associated with a pathogenic RING1 missense variant implicate unappreciated functions. Using an in vitro model of neurodevelopment, we observe that RING1 contributes to the broad placement of H2AK119ub1, and that its targets overlap with those of RNF2. PRC1 complexes harboring hypomorphic RING1 bind target loci but do not catalyze H2AK119ub1, reducing H2AK119ub1 by preventing catalytically active complexes from accessing the locus. This results in delayed DNA damage repair and cell cycle progression in neural progenitor cells (NPCs). Conversely, reduced H2AK119ub1 due to hypomorphic RING1 does not generate differential expression that impacts NPC differentiation. In contrast, hypomorphic RNF2 generates a greater reduction in H2AK119ub1 that results in both delayed DNA repair and widespread transcriptional changes. These findings suggest that the DNA damage response is more sensitive to H2AK119ub1 dosage change than is regulation of gene expression.

多梳抑制复合物 1 （PRC1） 通过催化组蛋白 H2A 赖氨酸 119 单泛素化 （H2AK119ub1） 修饰染色质。RING1 和 RNF2 可互换地作为 PRC1 中的催化亚基。PRC1 核心组分中的致病性错义变异揭示了这些蛋白质的功能，这些蛋白质在敲除模型中被掩盖了。虽然 Ring1a 敲除模型保持健康，但与致病性 RING1 错义变异相关的小头畸形和神经精神表型暗示了未被重视的功能。使用神经发育的体外模型，我们观察到 RING1 有助于 H2AK119ub1 的广泛放置，并且其靶标与 RNF2 的靶标重叠。携带亚态性 RING1 的 PRC1 复合物结合靶基因座，但不催化 H2AK119ub1，通过阻止催化活性复合物进入基因座来减少 H2AK119ub1。这会导致神经祖细胞 （NPC） 的 DNA 损伤修复延迟和细胞周期进程。相反，由于亚型 RING1 导致的 H2AK119ub1 减少不会产生影响 NPC 分化的差异表达。相比之下，亚态性 RNF2 产生更大的 H2AK119ub1 减少，从而导致 DNA 修复延迟和广泛的转录变化。这些发现表明，DNA 损伤反应对 H2AK119ub1 剂量变化比对基因表达的调节更敏感。