Mechanisms of functional cross-talk between global transcriptional repression and efficient DNA damage repair during genotoxic stress are poorly known. In this study, using human AF9 as representative of Super Elongation Complex (SEC) components, we delineate detailed mechanisms of these processes. Mechanistically, we describe that Poly-Serine domain-mediated oligomerization is pre-requisite for AF9 YEATS domain-mediated TFIID interaction-dependent SEC recruitment at the promoter-proximal region for release of paused RNA polymerase II. Interestingly, during genotoxic stress, CaMKII-mediated phosphorylation-dependent nuclear export of AF9-specific deacetylase HDAC5 enhances concomitant PCAF-mediated acetylation of K339 residue. This causes monomerization of AF9 and reduces TFIID interaction for transcriptional downregulation. Furthermore, the K339 acetylation-dependent enhanced AF9-DNA-PKc interaction leads to phosphorylation at S395 residue which reduces AF9-SEC interaction resulting in transcriptional downregulation and efficient repair of DNA damage. After repair, nuclear re-entry of HDAC5 reduces AF9 acetylation and restores its TFIID and SEC interaction to restart transcription.

基因毒性应激期间整体转录抑制和有效 DNA 损伤修复之间的功能串扰机制尚不清楚。在这项研究中，我们使用人类 AF9 作为超级伸长复合物 (SEC) 成分的代表，描述了这些过程的详细机制。从机制上讲，我们描述了聚丝氨酸结构域介导的寡聚化是 AF9 YEATS 结构域介导的 TFIID 相互作用依赖性 SEC 在启动子近端区域招募以释放暂停的 RNA 聚合酶 II 的先决条件。有趣的是，在基因毒性应激期间，CaMKII 介导的 AF9 特异性脱乙酰酶 HDAC5 的磷酸化依赖性核输出增强了伴随的 PCAF 介导的 K339 残基乙酰化。这会导致 AF9 单体化并减少 TFIID 相互作用以实现转录下调。此外，K339 乙酰化依赖性增强的 AF9-DNA-PKc 相互作用导致 S395 残基磷酸化，从而减少 AF9-SEC 相互作用，从而导致转录下调和 DNA 损伤的有效修复。修复后，HDAC5 重新进入核会减少 AF9 乙酰化并恢复其 TFIID 和 SEC 相互作用以重新启动转录。