Rembiałkowska Nina, Rekiel Katarzyna, Urbanowicz Piotr, Mamala Mateusz, Marczuk Karolina, Wojtaszek Maria, Żywica Marta, Radzevičiūtė-Valčiukė Eivina, Novickij Vitalij, Kulbacka Julita
Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland.
Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland.
Int J Mol Sci. 2025 Jul 7;26(13):6531. doi: 10.3390/ijms26136531.
Epigenetic modifications are heritable, reversible alterations that causally reshape chromatin architecture and thereby influence DNA repair without changing nucleotide sequence. DNA methylation, histone modifications and non-coding RNAs profoundly influence DNA repair mechanisms and genomic stability. Aberrant epigenetic patterns in cancer compromise DNA damage recognition and repair, therefore impairing homologous recombination (HR), non-homologous end joining (NHEJ), and base excision repair (BER) by suppressing key repair genes and lowering access to repair sites. Then it is dissected how loss-of-function mutations in Switch/Sucrose non-fermentable, imitation switch and CHD (Chromodomain helicase DNA-binding) chromatin-remodeling complexes impair nucleosome repositioning, preventing effective damage sensing and assembly of repair machinery. Non-coding RNAs contribute to epigenetic silencing at DNA break sites, exacerbating repair deficiencies. This review evaluates recent advances concerning epigenetic dysfunction and DNA repair impairment. It is also highlighted that nanoparticle-mediated delivery strategies are designed to overcome pharmacologic resistance. It is presented how epigenetic dysregulation of DNA repair can guide more effective and drug-resistant cancer therapies.
表观遗传修饰是可遗传的、可逆的改变，它通过重塑染色质结构从而在不改变核苷酸序列的情况下影响DNA修复。DNA甲基化、组蛋白修饰和非编码RNA对DNA修复机制和基因组稳定性有深远影响。癌症中异常的表观遗传模式会损害DNA损伤识别和修复，从而通过抑制关键修复基因并减少对修复位点的 access，损害同源重组（HR）、非同源末端连接（NHEJ）和碱基切除修复（BER）。接着剖析了Switch/Sucrose non-fermentable、imitation switch和CHD（染色质结构域解旋酶DNA结合）染色质重塑复合物中的功能丧失突变如何损害核小体重新定位，阻止有效的损伤感知和修复机制的组装。非编码RNA导致DNA断裂位点的表观遗传沉默，加剧修复缺陷。本综述评估了表观遗传功能障碍和DNA修复损伤的最新进展。还强调了纳米颗粒介导的递送策略旨在克服耐药性。展示了DNA修复的表观遗传失调如何指导更有效和抗耐药的癌症治疗。
