Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI, USA.
Medical Science Training Program, University of Michigan Medical School, Ann Arbor, MI, USA.
Nat Commun. 2024 Sep 10;15(1):7931. doi: 10.1038/s41467-024-52292-8.
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）来修饰染色质。RING1 和 RNF2 可互换作为 PRC1 中的催化亚基。PRC1 核心成分中的致病性错义变体揭示了这些蛋白质的功能，这些功能在敲除模型中被掩盖了。虽然 Ring1a 敲除模型仍然健康，但与致病性 RING1 错义变体相关的小头畸形和神经精神表型表明存在未被认识到的功能。使用体外神经发育模型，我们观察到 RING1 有助于 H2AK119ub1 的广泛定位，并且其靶标与 RNF2 的靶标重叠。携带功能减弱的 RING1 的 PRC1 复合物结合靶标位点，但不催化 H2AK119ub1，通过阻止催化活性复合物进入位点来减少 H2AK119ub1，从而导致神经祖细胞（NPC）中的 DNA 损伤修复和细胞周期进程延迟。相反，由于功能减弱的 RING1 导致 H2AK119ub1 减少，不会产生影响 NPC 分化的差异表达。相比之下，功能减弱的 RNF2 会导致 H2AK119ub1 更大幅度的减少，从而导致 DNA 修复延迟和广泛的转录变化。这些发现表明，与基因表达调控相比，DNA 损伤反应对 H2AK119ub1 剂量变化更敏感。
