MIF is a 3’ flap nuclease that facilitates DNA replication and promotes tumor growth

Author:

Wang YijieORCID,Chen Yan,Wang Chenliang,Yang Mingming,Wang Yanan,Bao Lei,Wang Jennifer E.,Kim BongWoo,Chan Kara Y.,Xu Weizhi,Capota Emanuela,Ortega JaniceORCID,Nijhawan Deepak,Li Guo-MinORCID,Luo WeiboORCID,Wang YingfeiORCID

Abstract

AbstractHow 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.

Funder

U.S. Department of Health & Human Services | NIH | National Cancer Institute

Cancer Prevention and Research Institute of Texas

Susan G. Komen

Mary Kay Foundation

Welch Foundation

U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke

U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences

U.S. Department of Health & Human Services | NIH | National Institute on Aging

Darrell K Royal Research Fund

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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