Essential histone chaperones collaborate to regulate transcription and chromatin integrity

Histone chaperones are critical for controlling chromatin integrity during transcription, DNA replication, and DNA repair. We have discovered that the physical interaction between two essential histone chaperones, Spt6 and Spn1/Iws1, is required for transcriptional accuracy and nucleosome organization. To understand this requirement, we have isolated suppressors of an spt6 mutation that disrupts the Spt6-Spn1 interaction. Several suppressors are in a third essential histone chaperone, FACT, while another suppressor is in the transcription elongation factor Spt5/DSIF. The FACT suppressors weaken FACT-nucleosome interactions and bypass the requirement for Spn1, possibly by restoring a necessary balance between Spt6 and FACT on chromatin. In contrast, the Spt5 suppressor modulates Spt6 function in a Spn1-dependent manner. Despite these distinct mechanisms, both suppressors alleviate the nucleosome organization defects caused by disruption of the Spt6-Spn1 interaction. Taken together, we have uncovered a network in which histone chaperones and other elongation factors coordinate transcriptional integrity and chromatin structure.组蛋白伴侣（histone chaperones）在转录、DNA复制与DNA修复过程中，对维持染色质完整性发挥关键调控作用。本研究发现，两种必需组蛋白伴侣Spt6与Spn1/Iws1之间的物理相互作用，是保障转录保真度与核小体组织的必要条件。为阐明该相互作用的必要性，我们针对破坏Spt6-Spn1相互作用的spt6突变体，分离得到了其抑制子。其中多个抑制子位于第三种必需组蛋白伴侣FACT中，另一个抑制子则存在于转录延伸因子Spt5/DSIF内。FACT相关抑制子可削弱FACT与核小体的相互作用，并绕过对Spn1的需求，其潜在机制为恢复染色质上Spt6与FACT间的必要平衡。与之相反，Spt5相关抑制子则以Spn1依赖的方式调控Spt6的功能。尽管二者作用机制截然不同，但两种抑制子均能缓解由Spt6-Spn1相互作用破坏所引发的核小体组织缺陷。综上，我们揭示了一个由组蛋白伴侣与其他转录延伸因子协同调控转录保真度与染色质结构的调控网络。