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1.
Carcinogenesis ; 43(2): 160-169, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-34919656

RESUMO

The prevalent cancer predisposition Lynch syndrome (LS, OMIM #120435) is caused by an inherited heterozygous defect in any of the four core DNA mismatch repair (MMR) genes MSH2, MSH6, MLH1 or PMS2. MMR repairs errors by the replicative DNA polymerases in all proliferating tissues. Its deficiency, following somatic loss of the wild-type copy, results in a spontaneous mutator phenotype that underlies the rapid development of, predominantly, colorectal cancer (CRC) in LS. Here, we have addressed the hypothesis that aberrant responses of intestinal stem cells to diet-derived mutagens may be causally involved in the restricted cancer tropism of LS. To test this we have generated a panel of isogenic mouse embryonic stem (mES) cells with heterozygous or homozygous disruption of multiple MMR genes and investigated their responses to the common dietary mutagen and carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Our data reveal that PhIP can inactivate the wild-type allele of heterozygous mES cells via the induction of either loss of heterozygosity (LOH) or intragenic mutations. Moreover, while protective DNA damage signaling (DDS) is compromised, PhIP induces more mutations in Msh2, Mlh1, Msh6 or Pms2-deficient mES cells than in wild-type cells. Combined with their spontaneous mutator phenotypes, this results in a compound hypermutator phenotype. Together, these results indicate that dietary mutagens may promote CRC development in LS at multiple levels, providing a rationale for dietary modifications in the management of LS.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Animais , Neoplasias Encefálicas , Neoplasias Colorretais , Neoplasias Colorretais Hereditárias sem Polipose/genética , Dano ao DNA , Reparo de Erro de Pareamento de DNA/genética , Proteínas de Ligação a DNA/genética , Dieta/efeitos adversos , Mutação em Linhagem Germinativa , Camundongos , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Mutagênicos/toxicidade , Síndromes Neoplásicas Hereditárias
2.
DNA Repair (Amst) ; 93: 102923, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-33087264

RESUMO

Canonical DNA mismatch repair (MMR) excises base-base mismatches to increase the fidelity of DNA replication. Thus, loss of MMR leads to increased spontaneous mutagenesis. MMR genes also are involved in the suppression of mutagenic, and the induction of protective, responses to various types of DNA damage. In this review we describe these non-canonical roles of MMR at different lesion types. Loss of non-canonical MMR gene functions may have important ramifications for the prevention, development and treatment of colorectal cancer associated with inherited MMR gene defects in Lynch syndrome. This graphical review pays tribute to Samuel H. Wilson. Sam not only made seminal contributions to understanding base excision repair, particularly with respect to structure-function relationships in DNA polymerase ß but also, as Editor of DNA Repair, has maintained a high standard of the journal.


Assuntos
Neoplasias Colorretais/genética , Dano ao DNA , Reparo de Erro de Pareamento de DNA , Neoplasias Colorretais Hereditárias sem Polipose , DNA/metabolismo , Replicação do DNA , Humanos , Mutagênese
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