title: Loss of DNA mismatch repair imparts a selective advantage in planarian adult stem cells.
abstract: Lynch syndrome (LS) leads to an increased risk of early-onset colorectal and other types of cancer and is caused by germline mutations in DNA mismatch repair (MMR) genes. Loss of MMR function results in a mutator phenotype that likely underlies its role in tumorigenesis. However, loss of MMR also results in the elimination of a DNA damage-induced checkpoint/apoptosis activation barrier that may allow damaged cells to grow unchecked. A fundamental question is whether loss of MMR provides pre-cancerous stem cells an immediate selective advantage in addition to establishing a mutator phenotype. To test this hypothesis in an in vivo system, we utilized the planarian Schmidtea mediterranea which contains a significant population of identifiable adult stem cells. We identified a planarian homolog of human MSH2, a MMR gene which is mutated in 38% of LS cases. The planarian Smed-msh2 is expressed in stem cells and some progeny. We depleted Smed-msh2 mRNA levels by RNA-interference and found a striking survival advantage in these animals treated with a cytotoxic DNA alkylating agent compared to control animals. We demonstrated that this tolerance to DNA damage is due to the survival of mitotically active, MMR-deficient stem cells. Our results suggest that loss of MMR provides an in vivo survival advantage to the stem cell population in the presence of DNA damage that may have implications for tumorigenesis.
authors: University of Connecticut Health Center, Farmington, Connecticut, United States of America.
authors: Jessica P
authors: JP
authors: Hollenbach
authors: Alissa M
authors: AM
authors: Resch
authors: Dasaradhi
authors: D
authors: Palakodeti
authors: Brenton R
authors: BR
authors: Graveley
authors: Christopher D
authors: CD
authors: Heinen
mesh_terms: D053687:Adult Stem Cells / Q000187:drug effects / Q000378:metabolism*; D000477:Alkylating Agents / Q000633:toxicity; D000595:Amino Acid Sequence; D000818:Animals; D004249:DNA Damage / Q000235:genetics; D053843:DNA Mismatch Repair / Q000187:drug effects / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D008969:Molecular Sequence Data; D010932:Planarians / Q000166:cytology* / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D034622:RNA Interference; D012038:Regeneration / Q000187:drug effects / Q000235:genetics; D012641:Selection, Genetic; D012689:Sequence Homology, Nucleic Acid
chemical_list: D000477:Alkylating Agents; D004268:DNA-Binding Proteins