Mukhopadhyay Sudit S, Leung Kathryn S, Hicks M John, Hastings Philip J, Youssoufian Hagop, Plon Sharon E
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
J Cell Biol. 2006 Oct 23;175(2):225-35. doi: 10.1083/jcb.200607061.
Cells from patients with Fanconi anemia (FA), an inherited disorder that includes bone marrow failure and cancer predisposition, have increased sensitivity to oxidative stress through an unknown mechanism. We demonstrate that the FA group G (FANCG) protein is found in mitochondria. Wild-type but not G546R mutant FANCG physically interacts with the mitochondrial peroxidase peroxiredoxin-3 (PRDX3). PRDX3 is deregulated in FA cells, including cleavage by a calpainlike cysteine protease and mislocalization. FA-G cells demonstrate distorted mitochondrial structures, and mitochondrial extracts have a sevenfold decrease in thioredoxin-dependent peroxidase activity. Transient overexpression of PRDX3 suppresses the sensitivity of FA-G cells to H2O2, and decreased PRDX3 expression increases sensitivity to mitomycin C. Cells from the FA-A and -C subtypes also have PRDX3 cleavage and decreased peroxidase activity. This study demonstrates a role for the FA proteins in mitochondria witsh sensitivity to oxidative stress resulting from diminished peroxidase activity. These defects may lead to apoptosis and the accumulation of oxidative DNA damage in bone marrow precursors.
范可尼贫血（FA）是一种遗传性疾病，包括骨髓衰竭和癌症易感性，FA患者的细胞通过未知机制对氧化应激的敏感性增加。我们证明FA组G（FANCG）蛋白存在于线粒体中。野生型而非G546R突变型FANCG与线粒体过氧化物酶过氧化物还原酶3（PRDX3）发生物理相互作用。PRDX3在FA细胞中失调，包括被一种钙蛋白酶样半胱氨酸蛋白酶切割和定位错误。FA - G细胞表现出线粒体结构扭曲，线粒体提取物中硫氧还蛋白依赖性过氧化物酶活性降低七倍。PRDX3的瞬时过表达可抑制FA - G细胞对H2O2的敏感性，而PRDX3表达降低会增加对丝裂霉素C的敏感性。FA - A和 - C亚型的细胞也存在PRDX3切割和过氧化物酶活性降低的情况。这项研究证明了FA蛋白在线粒体中的作用，其对由于过氧化物酶活性降低导致的氧化应激敏感。这些缺陷可能导致骨髓前体细胞凋亡和氧化性DNA损伤的积累。
