Repair of double strand breaks (DSBs) by RNA-binding proteins (RBPs) is vital for ensuring genome integrity. DSB repair is accompanied by local transcriptional repression in the vicinity of transcriptionally active genes, but the mechanism by which RBPs regulate transcriptional regulation is unclear. Here, we demonstrated that RBP hnRNPA2B1 functions as a RNA polymerase-associated factor that stabilizes the transcription complex under physiological conditions. Following a DSB, hnRNPA2B1 is released from damaged chromatin, reducing the efficiency of RNAPII complex assembly, leading to local transcriptional repression. Mechanistically, SIRT6 deacetylates hnRNPA2B1 at K113/173 residues, enforcing its rapid detachment from DSBs. This process disrupts the integrity of the RNAPII complex on active chromatin, which is a pre-requisite for transient but complete repression of local transcription. Functionally, the overexpression of an acetylation mimic stabilizes the transcription complex and facilitates the functioning of the transcription machinery. hnRNPA2B1 acetylation status was negatively correlated with SIRT6 expression, and acetylation mimic enhanced radio-sensitivity in vivo. Our findings demonstrate that hnRNPA2B1 is crucial for transcriptional repression. We have uncovered the missing link between DSB repair and transcriptional regulation in genome stability maintenance, highlighting the potential of hnRNPA2B1 as a therapeutic target.

通过 RNA 结合蛋白 （RBP） 修复双链断裂 （DSB） 对于确保基因组完整性至关重要。DSB 修复伴随着转录活性基因附近的局部转录抑制，但 RBP 调节转录调控的机制尚不清楚。在这里，我们证明了 RBP hnRNPA2B1 作为 RNA 聚合酶相关因子发挥作用，可在生理条件下稳定转录复合物。DSB 后，hnRNPA2B1 从受损的染色质中释放出来，降低了 RNAPII 复合物组装的效率，导致局部转录抑制。从机制上讲，SIRT6 在 K113/173 残基处使 hnRNPA2B1 脱乙酰，从而加强其与 DSB 的快速分离。这个过程破坏了活性染色质上 RNAPII 复合物的完整性，这是短暂但完全抑制局部转录的先决条件。在功能上，乙酰化模拟物的过表达稳定了转录复合物并促进了转录机制的功能。hnRNPA2B1 乙酰化状态与 SIRT6 表达呈负相关，乙酰化模拟体内增强的放射敏感性。我们的研究结果表明，hnRNPA2B1 对转录抑制至关重要。我们发现了 DSB 修复和转录调控在基因组稳定性维持中缺失的联系，突出了 hnRNPA2B1 作为治疗靶点的潜力。