Department of Pediatrics, Section of Pediatric Hematology-Oncology, Wells Center for Pediatric Research, Indiana University School of Medicine, 1044 W Walnut Street, R4-421, Indianapolis, Indiana 46202, USA.
Riley Hospital for Children at Indiana University Health, 705 Riley Hospital Drive, Room 5900, Indianapolis, Indiana 46202, USA.
Nat Rev Cancer. 2018 Mar;18(3):168-185. doi: 10.1038/nrc.2017.116. Epub 2018 Jan 29.
Fanconi anaemia (FA) is a genetic disorder that is characterized by bone marrow failure (BMF), developmental abnormalities and predisposition to cancer. Together with other proteins involved in DNA repair processes and cell division, the FA proteins maintain genome homeostasis, and germline mutation of any one of the genes that encode FA proteins causes FA. Monoallelic inactivation of some FA genes, such as FA complementation group D1 (FANCD1; also known as the breast and ovarian cancer susceptibility gene BRCA2), leads to adult-onset cancer predisposition but does not cause FA, and somatic mutations in FA genes occur in cancers in the general population. Carcinogenesis resulting from a dysregulated FA pathway is multifaceted, as FA proteins monitor multiple complementary genome-surveillance checkpoints throughout interphase, where monoubiquitylation of the FANCD2-FANCI heterodimer by the FA core complex promotes recruitment of DNA repair effectors to chromatin lesions to resolve DNA damage and mitosis. In this Review, we discuss how the FA pathway safeguards genome integrity throughout the cell cycle and show how studies of FA have revealed opportunities to develop rational therapeutics for this genetic disease and for malignancies that acquire somatic mutations within the FA pathway.
范可尼贫血症（FA）是一种遗传性疾病，其特征是骨髓衰竭（BMF）、发育异常和易患癌症。FA 蛋白与其他参与 DNA 修复过程和细胞分裂的蛋白质一起，维持基因组的内稳态，任何一个编码 FA 蛋白的基因突变都会导致 FA。一些 FA 基因的单等位基因失活，如 FA 补体组 D1（FANCD1；也称为乳腺癌和卵巢癌易感基因 BRCA2），导致成年期易患癌症，但不会导致 FA，FA 基因的体细胞突变发生在普通人群的癌症中。FA 途径失调导致的癌变是多方面的，因为 FA 蛋白在整个间期中监测多个互补的基因组监测检查点，FA 核心复合物将 FANCD2-FANCI 异二聚体单泛素化，促进 DNA 修复效应器募集到染色质损伤处，以解决 DNA 损伤和有丝分裂。在这篇综述中，我们讨论了 FA 途径如何在整个细胞周期中保护基因组完整性，并展示了 FA 研究如何为这种遗传疾病和获得 FA 途径中体细胞突变的恶性肿瘤提供合理的治疗方法。
