Preservation of ALYREF Phase Separation Mitigates Doxorubicin‐Induced Cardiomyocyte DNA Damage and Cardiotoxicity

心脏毒性 阿霉素 DNA损伤 相(物质) DNA 化学 内科学 医学 毒性 生物化学 化疗 有机化学
作者
Xinlu Gao,Yifu Shen,Zhihui Xiao,Zhenbo Han,Xu Liu,Ao Cai,Yanan Tian,Guang Lian,Wenya Ma,Yining Liu,Yining Liu,Rui Gong,Hanjing Li,Xiuxiu Wang,Zhongyu Ren,Naufal Sh. Zagidullin,Lei Yu,Ye Tian,Yu Liu,Yu Liu
出处
期刊:Advanced Science [Wiley]
卷期号:12 (43): e05270-e05270 被引量:3
标识
DOI:10.1002/advs.202505270
摘要

The clinical utility of the anticancer agent doxorubicin (DOX) is limited by its dose-dependent cardiotoxicity. ALYREF, a nuclear protein that preserves genomic stability through interactions with intranuclear components or as an m⁵C-binding regulator of mRNA maturation and export, has not been previously implicated in DOX-induced cardiotoxicity (DIC). Here, the role and underlying mechanisms of ALYREF in the pathogenesis of DIC are investigated. The findings demonstrate that ALYREF expression is markedly reduced in a murine model of DIC. Myocardial-specific overexpression of ALYREF attenuates DOX-induced DNA damage and cardiomyocyte apoptosis, whereas cardiac-specific knockout of ALYREF (ALYREF CKO) exacerbates DOX-induced cardiac dysfunction. Mechanistically, it is identified that nuclear DOX directly binds to the aspartate residue (D171) within the intrinsically disordered regions (IDRs) of ALYREF, disrupting its liquid-liquid phase separation (LLPS) and promoting its ubiquitin-mediated degradation. The condensate state of ALYREF is essential for maintaining the integrity of the NORAD-activated ribonucleoprotein complex 1 (NARC1). Consequently, disruption of ALYREF LLPS leads to dissociation of the NARC1 complex, resulting in DNA damage and apoptosis in CMs. Collectively, these findings reveal a previously unrecognized mechanism by which DIC via interference with ALYREF condensates, offering new insight into the molecular basis of DIC.
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