MRN复合体的多面性：在髓母细胞瘤及其他方面的作用

The Multiple Faces of the MRN Complex: Roles in Medulloblastoma and Beyond.

作者信息

Petroni Marialaura, La Monica Veronica, Fabretti Francesca, Augusto Mariaconcetta, Battaglini Damiana, Polonara Francesca, Di Giulio Stefano, Giannini Giuseppe

机构信息

Department of Molecular Medicine, University La Sapienza, 00161 Rome, Italy.

Istituto Pasteur-Fondazione Cenci Bolognetti, 00161 Rome, Italy.

出版信息

Cancers (Basel). 2023 Jul 13;15(14):3599. doi: 10.3390/cancers15143599.

DOI:10.3390/cancers15143599

PMID:37509263

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10377613/

Abstract

Hypomorphic mutations in MRN complex genes are frequently found in cancer, supporting their role as oncosuppressors. However, unlike canonical oncosuppressors, MRN proteins are often overexpressed in tumor tissues, where they actively work to counteract DSBs induced by both oncogene-dependent RS and radio-chemotherapy. Moreover, at the same time, genes are also essential genes, since the constitutive KO of each component leads to embryonic lethality. Therefore, even though it is paradoxical, genes may work as oncosuppressive, oncopromoting, and essential genes. In this review, we discussed how alterations in the MRN complex impact the physiopathology of cancer, in light of our recent discoveries on the gene-dosage-dependent effect of NBS1 in Medulloblastoma. These updates aim to understand whether MRN complex can be realistically used as a prognostic/predictive marker and/or as a therapeutic target for the treatment of cancer patients in the future.

摘要

MRN复合物基因中的低表达突变在癌症中经常被发现，这支持了它们作为肿瘤抑制因子的作用。然而，与典型的肿瘤抑制因子不同，MRN蛋白在肿瘤组织中常常过度表达，在那里它们积极发挥作用以对抗由癌基因依赖性复制应激和放化疗诱导的双链断裂。此外，与此同时，这些基因也是必需基因，因为每个组分的组成型敲除都会导致胚胎致死。因此，尽管看似矛盾，但这些基因可能同时起到肿瘤抑制、肿瘤促进和必需基因的作用。在这篇综述中，鉴于我们最近关于NBS1在髓母细胞瘤中的基因剂量依赖性效应的发现，我们讨论了MRN复合物的改变如何影响癌症的生理病理学。这些更新旨在了解MRN复合物未来是否真的可以用作预后/预测标志物和/或癌症患者治疗的治疗靶点。