K Jagadeesh Chandra Bose, Kapoor Bishwajit Singh, Mandal Kamal, Ghosh Shubhrima, Mokhamatam Raveendra B, Manna Sunil K, Mukhopadhyay Sudit S
Department of Biotechnology, National Institute of Technology Durgapur, Durgapur, West Bengal, India.
Center for DNA Finger Printing and Diagnostics, Hyderabad, India.
Mol Cell Biol. 2020 Nov 6;40(23). doi: 10.1128/MCB.00306-20.
Fanconi anemia (FA) is a unique DNA damage repair pathway. To date, 22 genes have been identified that are associated with the FA pathway. A defect in any of those genes causes genomic instability, and the patients bearing the mutation become susceptible to cancer. In our earlier work, we identified that Fanconi anemia protein G (FANCG) protects the mitochondria from oxidative stress. In this report, we have identified eight patients having a mutation (C.65G>C), which converts arginine at position 22 to proline (p.Arg22Pro) in the N terminus of FANCG. The mutant protein, hFANCGR22P, is able to repair the DNA and able to retain the monoubiquitination of FANCD2 in the FANCGR22P/FGR22P cell. However, it lost mitochondrial localization and failed to protect mitochondria from oxidative stress. Mitochondrial instability in the FANCGR22P cell causes the transcriptional downregulation of mitochondrial iron-sulfur cluster biogenesis protein frataxin (FXN) and the resulting iron deficiency of FA protein FANCJ, an iron-sulfur-containing helicase involved in DNA repair.
范可尼贫血（FA）是一种独特的DNA损伤修复途径。迄今为止，已鉴定出22个与FA途径相关的基因。这些基因中的任何一个存在缺陷都会导致基因组不稳定，携带该突变的患者易患癌症。在我们早期的研究中，我们发现范可尼贫血蛋白G（FANCG）可保护线粒体免受氧化应激。在本报告中，我们鉴定出8名患者存在一种突变（C.65G>C），该突变使FANCG N端第22位的精氨酸转变为脯氨酸（p.Arg22Pro）。突变蛋白hFANCGR22P能够修复DNA，并能在FANCGR22P/FGR22P细胞中保持FANCD2的单泛素化。然而，它失去了线粒体定位，无法保护线粒体免受氧化应激。FANCGR22P细胞中的线粒体不稳定导致线粒体铁硫簇生物合成蛋白弗里德赖希共济失调蛋白（FXN）转录下调，进而导致参与DNA修复的含硫铁解旋酶FA蛋白FANCJ铁缺乏。
