Ramadan Wafaa S, Ahmed Samrein B M, Talaat Iman M, Lozon Lama, Mouffak Soraya, Gemoll Timo, Mansour Wael Y, El-Awady Raafat
Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates.
College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.
Genome Biol. 2025 Apr 8;26(1):89. doi: 10.1186/s13059-025-03528-3.
Spatial and temporal control of DNA damage response pathways after DNA damage is crucial for maintenance of genomic stability. Ataxia telangiectasia mutated (ATM) protein plays a central role in DNA damage response pathways. The chain of events following induction of DNA damage that results in full activation of ATM is still evolving. Here we set out to explore the role of CREB-binding protein (CBP), a histone acetyltransferase (HAT), in DNA damage response, particularly in the ATM activation pathway.
In response to DNA damage, CBP is stabilized and is recruited at sites of DNA double-strand breaks where it acetylates ATM and promotes its kinase activity. Cells deficient in CBP display an impairment in DNA double-strand break repair and high sensitivity to chemo- and radiotherapy. Importantly, re-expressing CBP's HAT domain in CBP-deficient cells restores the DNA repair capability, demonstrating the essential role of CBP's HAT domain in repairing DNA double-strand breaks.
Together, our findings shed the light on CBP as a key participant in the ATM activation pathway and in the subsequent repair of DNA double-strand breaks, which may serve as a potential target to modulate the cellular response to DNA damaging agents in cancer.
DNA损伤后DNA损伤反应通路的时空控制对于维持基因组稳定性至关重要。共济失调毛细血管扩张症突变（ATM）蛋白在DNA损伤反应通路中起核心作用。导致ATM完全激活的DNA损伤诱导后一系列事件仍在不断演变。在此，我们着手探究CREB结合蛋白（CBP），一种组蛋白乙酰转移酶（HAT），在DNA损伤反应中的作用，特别是在ATM激活通路中的作用。
响应DNA损伤时，CBP稳定并被招募至DNA双链断裂位点，在该位点它使ATM乙酰化并促进其激酶活性。CBP缺陷的细胞在DNA双链断裂修复方面存在缺陷，并且对化疗和放疗高度敏感。重要的是，在CBP缺陷细胞中重新表达CBP的HAT结构域可恢复DNA修复能力，证明CBP的HAT结构域在修复DNA双链断裂中起关键作用。
总之，我们的研究结果揭示了CBP作为ATM激活通路及随后DNA双链断裂修复的关键参与者，这可能成为调节癌症细胞对DNA损伤剂反应的潜在靶点。
