Chakraborty Sharmistha, Singh Mayank, Pandita Raj K, Singh Vipin, Lo Calvin S C, Leonard Fransisca, Horikoshi Nobuo, Moros Eduardo G, Guha Deblina, Hunt Clayton R, Chau Eric, Ahmed Kazi M, Sethi Prayas, Charaka Vijaya, Godin Biana, Makhijani Kalpana, Scherthan Harry, Deck Jeanette, Hausmann Michael, Mushtaq Arjamand, Altaf Mohammad, Ramos Kenneth S, Bhat Krishna M, Taneja Nitika, Das Chandrima, Pandita Tej K
Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030, USA.
Department of Radiation Oncology, University of Texas Southwestern Medical Centre, Dallas, TX, USA.
iScience. 2022 Mar 23;25(4):104142. doi: 10.1016/j.isci.2022.104142. eCollection 2022 Apr 15.
Hyperthermia inhibits DNA double-strand break (DSB) repair that utilizes homologous recombination (HR) pathway by a poorly defined mechanism(s); however, the mechanisms for this inhibition remain unclear. Here we report that hyperthermia decreases H4K16 acetylation (H4K16ac), an epigenetic modification essential for genome stability and transcription. Heat-induced reduction in H4K16ac was detected in humans, , and yeast, indicating that this is a highly conserved response. The examination of histone deacetylase recruitment to chromatin after heat-shock identified SIRT1 as the major deacetylase subsequently enriched at gene-rich regions. Heat-induced SIRT1 recruitment was antagonized by chromatin remodeler SMARCAD1 depletion and, like hyperthermia, the depletion of the SMARCAD1 or combination of the two impaired DNA end resection and increased replication stress. Altered repair protein recruitment was associated with heat-shock-induced γ-H2AX chromatin changes and DSB repair processing. These results support a novel mechanism whereby hyperthermia impacts chromatin organization owing to H4K16ac deacetylation, negatively affecting the HR-dependent DSB repair.
热疗通过尚不明确的机制抑制利用同源重组（HR）途径的DNA双链断裂（DSB）修复；然而，这种抑制的机制仍不清楚。在此我们报告，热疗会降低H4K16乙酰化（H4K16ac），这是一种对基因组稳定性和转录至关重要的表观遗传修饰。在人类、[此处原文缺失相关内容]和酵母中均检测到热诱导的H4K16ac减少，表明这是一种高度保守的反应。热休克后对组蛋白去乙酰化酶募集至染色质的检查确定SIRT1为随后在基因丰富区域富集的主要去乙酰化酶。染色质重塑因子SMARCAD1的缺失拮抗了热诱导的SIRT1募集，并且与热疗一样，SMARCAD1的缺失或两者的联合作用会损害DNA末端切除并增加复制应激。修复蛋白募集的改变与热休克诱导的γ-H2AX染色质变化及DSB修复过程相关。这些结果支持了一种新机制，即热疗由于H4K16ac去乙酰化而影响染色质组织，对依赖HR的DSB修复产生负面影响。
