Tumor progression in Apc(1638N) mice with Exo1 and Fen1 deficiencies.
Flap endonuclease 1 (Fen1) and exonuclease 1 (Exo1) have sequence homology and similar nuclease capabilities. Both function in multiple pathways of DNA metabolism, but appear to have distinct in vivo nucleic acid substrates, and therefore distinct metabolic roles. When combined with Apc(1638N), Fen1 promotes tumor progression. Because of functional similarity to Fen1, and because Exo1 is involved in DNA mismatch repair (MMR) by interaction with Msh2 and Mlh1, genes that cause hereditary nonpolyposis colorectal cancer (HNPCC), we investigated the possibility that Exo1 might also act as a modifier to Apc(1638N). We present evidence that mice with combined mutations in Apc(1638N) and Exo1 and Apc(1638N), Exo1 and Fen1 genes show moderate increased tumor incidence and multiplicity in comparison to Apc(1638N) siblings, implying a low penetrance role for Exo1 in early gastrointestinal (GI) tumorigenesis. Despite a decrease in median survival (10 months) in Apc(1638N) Exo1 mice, their tumors do not progress any more rapidly than those of Apc(1638N). Instead these animals die from infections that are the result of impaired immune response. Apc(1638N) Exo1 Fen1 mice survive longer (18 months), and therefore appear relatively immune competent. They die of invasive GI tumors that display microsatellite instability (MSI). Our results show that Exo1 has a modest tumor suppressor function.
Kucherlapati
M
M
Harvard-Partners Center for Genetics and Genomics, Harvard Medical School, Boston, MA 02115, USA. mkucherlapati@rics.bwh.harvard.edu
Nguyen
A
A
Kuraguchi
M
M
Yang
K
K
Fan
K
K
Bronson
R
R
Wei
K
K
Lipkin
M
M
Edelmann
W
W
Kucherlapati
R
R
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001216:Asparagine / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005090:Exodeoxyribonucleases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D045585:Flap Endonucleases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D017491:Genes, APC; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015996:Survival Rate
D025601:Adenomatous Polyposis Coli Protein; D001216:Asparagine; D005090:Exodeoxyribonucleases; D045585:Flap Endonucleases; C028450:exodeoxyribonuclease I