MIF is a 3' flap nuclease that facilitates DNA replication and promotes tumor growth.
MIF is a 3' flap nuclease that facilitates DNA replication and promotes tumor growth.
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DOI：
10.1038/s41467-021-23264-z
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发表时间：
2021-05-19
影响因子：
16.6
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Wang Y;Chen Y;Wang C;Yang M;Wang Y;Bao L;Wang JE;Kim B;Chan KY;Xu W;Capota E;Ortega J;Nijhawan D;Li GM;Luo W;Wang Y
目前尚不清楚癌细胞在快速增殖期间如何科普高水平的复制压力。在这里，我们表明，巨噬细胞移动抑制因子（MIF）是一个3'瓣核酸酶，易位到细胞核中的S期。聚（ADP-核糖）聚合酶1与MIF共定位于DNA复制叉，其中需要MIF核酸酶活性来解决复制应激并促进肿瘤生长。癌细胞中MIF缺失导致突变频率增加、细胞周期延迟以及DNA合成和细胞生长抑制，这可以通过恢复MIF来挽救，但不能通过核酸酶缺陷的MIF突变体。MIF在乳腺肿瘤中显著上调，并与患者的总体生存率低相关。我们认为MIF是一种独特的3'端核酸酶，在DNA合成过程中切除3'端的侧翼，有利于癌细胞逃避复制应激诱导的生长威胁。复制应激与癌症的形成和进展有关。在这里，作者揭示了巨噬细胞移动抑制因子（MIF）作为3'瓣核酸酶参与解决影响整体肿瘤进展的复制应激。
How cancer cells cope with high levels of replication stress during rapid proliferation is currently unclear. Here, we show that macrophage migration inhibitory factor (MIF) is a 3’ flap nuclease that translocates to the nucleus in S phase. Poly(ADP-ribose) polymerase 1 co-localizes with MIF to the DNA replication fork, where MIF nuclease activity is required to resolve replication stress and facilitates tumor growth. MIF loss in cancer cells leads to mutation frequency increases, cell cycle delays and DNA synthesis and cell growth inhibition, which can be rescued by restoring MIF, but not nuclease-deficient MIF mutant. MIF is significantly upregulated in breast tumors and correlates with poor overall survival in patients. We propose that MIF is a unique 3’ nuclease, excises flaps at the immediate 3’ end during DNA synthesis and favors cancer cells evading replication stress-induced threat for their growth. Replication stress is associated with cancer formation and progression. Here the authors reveal that the macrophage migration inhibitory factor (MIF) functions as 3’ flap nuclease involved in resolving replication stress affecting overall tumor progression.
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影响因子：
3.8
作者：
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通讯作者：
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影响因子：
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通讯作者：
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