Mammalian SNM1 is required for genome stability

A. W. Hemphill, D. Bruun, L. Thrun, Y. Akkari, Y. Torimaru, K. Hejna, P. M. Jakobs, J. Hejna, S. Jones, S. B. Olson, R. E. Moses

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

The protein encoded by SNM1 in Saccharomyces cerevisiae has been shown to act specifically in DNA interstrand crosslinks (ICL) repair. There are five mammalian homologs of SNM1, including Artemis, which is involved in V(D)J recombination. Cells from mice constructed with a disruption in the Snm1 gene are sensitive to the DNA interstrand crosslinker, mitomycin (MMC), as indicated by increased radial formation following exposure. The mice reproduce normally and have normal life spans. However, a partial perinatal lethality, not seen in either homozygous mutant alone, can be noted when the Snm1 disruption is combined with a Fancd2 disruption. To explore the role of hSNM1 and its homologs in ICL repair in human cells, we used siRNA depletion in human fibroblasts, with cell survival and chromosome radials as the end points for sensitivity following treatment with MMC. Depletion of hSNM1 increases sensitivity to ICLs as detected by both end points, while depletion of Artemis does not. Thus hSNM1 is active in maintenance of genome stability following ICL formation. To evaluate the epistatic relationship between hSNM1 and other ICL repair pathways, we depleted hSNM1 in Fanconi anemia (FA) cells, which are inherently sensitive to ICLs. Depletion of hSNM1 in an FA cell line produces additive sensitivity for MMC. Further, mono-ubiquitination of FANCD2, an endpoint of the FA pathway, is not disturbed by depletion of hSNM1 in normal cells. Thus, hSNM1 appears to represent a second pathway for genome stability, distinct from the FA pathway.

Original languageEnglish (US)
Pages (from-to)38-45
Number of pages8
JournalMolecular Genetics and Metabolism
Volume94
Issue number1
DOIs
StatePublished - May 2008

Keywords

  • Fanconi anemia
  • Genome stability
  • Interstrand crosslink repair
  • Radials
  • SNM1

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

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    Hemphill, A. W., Bruun, D., Thrun, L., Akkari, Y., Torimaru, Y., Hejna, K., Jakobs, P. M., Hejna, J., Jones, S., Olson, S. B., & Moses, R. E. (2008). Mammalian SNM1 is required for genome stability. Molecular Genetics and Metabolism, 94(1), 38-45. https://doi.org/10.1016/j.ymgme.2007.11.012