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

Yijie Wang, Yan Chen, Chenliang Wang, Mingming Yang, Yanan Wang, Lei Bao, Jennifer E. Wang, Bong Woo Kim, Kara Y. Chan, Weizhi Xu, Emanuela Capota, Janice Ortega, Deepak Nijhawan, Guo Min Li, Weibo Luo, Yingfei Wang

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number2954
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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