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DNMT1 knockout delivers a strong blow to genome stability and cell viability

Nature Genetics volume 39, pages 289–290 (2007)Cite this article

The DNA methyltransferase DNMT1 is essential for cell viability in various mouse models, but gene targeting in human tumor cells results in a viable line. This dilemma has now been resolved using a new human DNMT1 knockout line, although new questions arise as to the full extent of DNMT1 function in maintaining genome integrity.

DNMT1 is viewed as the maintenance DNA methyltransferase, as it interacts with proliferating cell nuclear antigen (PCNA) and is targeted to replication foci during S phase1. Mice deficient for Dnmt1 lose ∼90% of their DNA methylation and die early in embryogenesis2. Mouse embryonic stem cells deficient in Dnmt1, although viable, die when induced to differentiate, and Dnmt1 conditional knockout mouse fibroblasts die within a few cell divisions after gene deletion3,4. It was assumed that DNMT1 in human cells would also prove essential; however, HCT116 cells with disrupted DNMT1 continue to proliferate and maintain ∼80% of their genomic methylation5. This has fueled a controversy: was there a fundamental difference between humans and mice, or were there problems associated with the knockout strategy? Recent studies from three laboratories, including those of En Li and colleagues on page 391 of this issue6, have addressed this debate, and their results demonstrate that the requirement for DNMT1 in human tumor cells is remarkably similar to that of mouse cells.

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Figure 1: Phenotypic effects stemming from variable DNMT1 expression in mammalian cells.

Katie Ris

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  1. Kevin D. Brown and Keith D. Robertson are in the Department of Biochemistry and Molecular Biology and the University of Florida–Shands Cancer Center, University of Florida, Box 100245, 1600 S.W. Archer Rd., Gainesville, Florida 32610, USA. keithr@ufl.edu

    Kevin D Brown & Keith D Robertson

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  1. Kevin D Brown
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  2. Keith D Robertson
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Brown, K., Robertson, K. DNMT1 knockout delivers a strong blow to genome stability and cell viability. Nat Genet 39, 289–290 (2007). https://doi.org/10.1038/ng0307-289

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