Mammalian SNM1 is required for genome stability.
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.
Hemphill
A W
AW
Department of Molecular and Medical Genetics, Oregon Health & Sciences University, 3181 Sam Jackson Park Road, Portland, OR 97239, USA.
Bruun
D
D
Thrun
L
L
Akkari
Y
Y
Torimaru
Y
Y
Hejna
K
K
Jakobs
P M
PM
Hejna
J
J
Jones
S
S
Olson
S B
SB
Moses
R E
RE
D000818:Animals; D018797:Cell Cycle Proteins; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics*; D004706:Endodeoxyribonucleases / Q000235:genetics; D005090:Exodeoxyribonucleases; D005199:Fanconi Anemia / Q000235:genetics; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics*; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection
D018797:Cell Cycle Proteins; D052236:Fanconi Anemia Complementation Group D2 Protein; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C493741:DCLRE1B protein, human; C506064:Dclre1a protein, mouse; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases; D045643:DNA Repair Enzymes