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MIF is a 3' flap nuclease that facilitates DNA replication and promotes tumor growth.
- Source :
-
Nature communications [Nat Commun] 2021 May 19; Vol. 12 (1), pp. 2954. Date of Electronic Publication: 2021 May 19. - Publication Year :
- 2021
-
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.
- Subjects :
- Animals
Breast Neoplasms genetics
Breast Neoplasms pathology
Cell Line, Tumor
Cell Proliferation
DNA chemistry
DNA metabolism
DNA Damage
DNA Polymerase III genetics
DNA Polymerase III metabolism
DNA Replication genetics
Female
Flap Endonucleases deficiency
Flap Endonucleases genetics
Gene Knockout Techniques
Genomic Instability
HCT116 Cells
Humans
Intramolecular Oxidoreductases deficiency
Intramolecular Oxidoreductases genetics
Macrophage Migration-Inhibitory Factors deficiency
Macrophage Migration-Inhibitory Factors genetics
Male
Mice
Mice, Inbred NOD
Mice, SCID
Mutant Proteins genetics
Mutant Proteins metabolism
Nucleic Acid Conformation
Poly (ADP-Ribose) Polymerase-1 metabolism
S Phase
Substrate Specificity
Breast Neoplasms metabolism
DNA Replication physiology
Flap Endonucleases metabolism
Intramolecular Oxidoreductases metabolism
Macrophage Migration-Inhibitory Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 12
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 34012010
- Full Text :
- https://doi.org/10.1038/s41467-021-23264-z