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（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一起维持基因组稳态，而编码FA蛋白的任何一种基因的种系突变都会导致FA。一些FA基因的单等位基因失活，例如FA互补组D1（FANCD1；也称为乳腺癌和卵巢癌易感基因BRCA2），导致成人发病的癌症易感性，但不会引起FA，并且普通人群的癌症中会发生FA基因的体细胞突变。FA通路失调导致的致癌作用是多方面的，因为FA蛋白在整个相间监测多个互补的基因组监测检查点，其中FA核心复合物对FANCD2-FANCI异二聚体的单泛素化作用促进了DNA修复效应子募集到染色质损伤中，从而解决了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维护基因组完整性，并展示了FA的研究如何揭示出开发针对这种遗传疾病和在FA途径中获得体细胞突变的恶性肿瘤的合理疗法的机会。