FANCD2 protects against bone marrow injury from ferroptosis

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• 作者：Xinxin Song^a ; Yangchun Xie^a ; Rui Kang^a ; Wen Hou^b ; Xiaofang Sun^c ; Michael W. Epperly^b ; Joel S. Greenberger^b ; Daolin Tang^a ; ^c ; ^{tangd2@upmc.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：FANCD2 ; Ferroptosis ; Bone marrow ; DNA damage ; Iron ; Lipid peroxidation
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2016
• 出版时间：18 November 2016
• 年：2016
• 卷：480
• 期：3
• 页码：443-449
• 全文大小：1066 K

文摘

Bone marrow injury remains a serious concern in traditional cancer treatment. Ferroptosis is an iron- and oxidative-dependent form of regulated cell death that has become part of an emerging strategy for chemotherapy. However, the key regulator of ferroptosis in bone marrow injury remains unknown. Here, we show that Fanconi anemia complementation group D2 (FANCD2), a nuclear protein involved in DNA damage repair, protects against ferroptosis-mediated injury in bone marrow stromal cells (BMSCs). The classical ferroptosis inducer erastin remarkably increased the levels of monoubiquitinated FANCD2, which in turn limited DNA damage in BMSCs. FANCD2-deficient BMSCs were more sensitive to erastin-induced ferroptosis (but not autophagy) than FANCD2 wild-type cells. Knockout of FANCD2 increased ferroptosis-associated biochemical events (e.g., ferrous iron accumulation, glutathione depletion, and malondialdehyde production). Mechanically, FANCD2 regulated genes and/or expression of proteins involved in iron metabolism (e.g., FTH1, TF, TFRC, HAMP, HSPB1, SLC40A1, and STEAP3) and lipid peroxidation (e.g., GPX4). Collectively, these findings indicate that FANCD2 plays a novel role in the negative regulation of ferroptosis. FANCD2 could represent an amenable target for the development of novel anticancer therapies aiming to reduce the side effects of ferroptosis inducers.