Shuai Yang, Ruru Wang, Lingling Liu, Feng Xu, Xipeng Zhao, Zhicheng Yao, Jie Zhang, Xu Cheng, An Xu, Lijun Wu, Guoping Zhao
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引用次数: 0
Abstract
Ribonucleotide reductase M1 (RRM1), the catalytic subunit of ribonucleotide reductase, plays a pivotal role in converting ribonucleotides (NTP) into deoxyribonucleotides (dNTP), essential for DNA replication and repair. Elevated RRM1 expression is associated with various human cancers, correlating with poorer prognosis and reduced overall survival rates. Our previous study found that RRM1 will enter the nucleus to promote DNA damage repair. However, the underlying mechanism remains elusive. Here, we unveil a novel role of RRM1 in promoting homologous recombination (HR) by upregulating the expression of RAD51AP1, a critical HR factor, in an E2F1-dependent manner. We demonstrate that RRM1 interacts with USP11 in the cytoplasm, and the recruitment of RRM1 to LaminB1 induced by ionizing radiation (IR) facilitates the binding of USP11 to the nuclear pore complex (NPC), promoting USP11 entry into the nucleus. Upon nuclear translocation, USP11 binds to E2F1 and inhibits the ubiquitin-mediated degradation of E2F1, thereby enhancing the transcriptional expression of RAD51AP1. Moreover, a specific RRM1 mutant lacking amino acids 731-793, crucial for its interaction with USP11 and recruitment to LaminB1, exhibits a dominant-negative effect on RAD51AP1 expression and HR. Truncations of RRM1 fail to inhibit the ubiquitin-mediated degradation of E2F1 and cannot promote the E2F1-mediated transactivation of RAD51AP1. Lastly, the full length of RRM1, not truncations, enhances tumor cells' sensitivity to IR, underscoring its importance in radiotherapy resistance. Collectively, our results suggest a novel function of RRM1 in promoting HR-mediated DSB repair through positive regulation of RAD51AP1 transcription by direct interaction with USP11 and promoting subsequent USP11-mediated deubiquitination of E2F1. Our findings elucidate a previously unknown mechanism whereby RRM1 promotes HR-mediated DNA repair, presenting a potential therapeutic target for cancer treatment.
期刊介绍:
Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary.
Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.