Increased somatic recombination in methylation tolerant human cells with defective DNA mismatch repair

Ciotta, Carmela; Ceccotti, Sabrina; Aquilina, Gabriele; Humbert, Odile; Palombo, Fabio; Jiricny, Josef; Bignami, Margherita

doi:10.1006/jmbi.1997.1559

Cited by 39 publications

(30 citation statements)

References 63 publications

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“…Thus, a human HeLa subclone lacking expression of PMS2 was found to have an increased rate of somatic recombination between two copies of a selectable gene, in comparison to the MMR-proficient parental cell line. 93 Similarly, increased somatic recombination has been reported in Msh2-null mouse ES cells. 94 Lymphomas in Msh2-null mice may arise through chromosomal aberrations caused by this hyper-recombinogenic phenotype.…”

Section: Cell Death and Differentiationmentioning

confidence: 67%

Functional interactions and signaling properties of mammalian DNA mismatch repair proteins

2001

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The mismatch repair (MMR) system promotes genomic fidelity by repairing base-base mismatches, insertion-deletion loops and heterologies generated during DNA replication and recombination. This function is critically dependent on the assembling of multimeric complexes involved in mismatch recognition and signal transduction to downstream repair events. In addition, MMR proteins coordinate a complex network of physical and functional interactions that mediate other DNA transactions, such as transcription-coupled repair, base excision repair and recombination. MMR proteins are also involved in activation of cell cycle checkpoint and induction of apoptosis when DNA damage overwhelms a critical threshold. For this reason, they play a role in cell death by alkylating agents and other chemotherapeutic drugs, including cisplatin. Inactivation of MMR genes in hereditary and sporadic cancer is associated with a mutator phenotype and inhibition of apoptosis. In the future, a deeper understanding of the molecular mechanisms and functional interactions of MMR proteins will lead to the development of more effective cancer prevention and treatment strategies.

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Section: Cell Death and Differentiationmentioning

confidence: 67%

Functional interactions and signaling properties of mammalian DNA mismatch repair proteins

2001

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“…We first tested extracts of human HeLa clone 12 cells, which lack hPMS2 (22) and thus contain only hMutLh and hMutLg. As the former heterodimer is devoid of MMR activity in our in vitro MMR assay (31), any observed repair activity could be ascribed to hMutLg.…”

Section: Discussionmentioning

confidence: 99%

“…The hPMS2-deficient cell lines HeLa clone 12 (22) and Hec-1A (23) were kindly provided by Dr. Margherita Bignami (ISS, Rome, Italy). The cell line HEK293T was derived from HEK293 by immortalization with adenovirus 5 DNA and transfection with SV40 large T antigen (24).…”

Section: Human Cell Lines and Preparation Of Cell Extractsmentioning

confidence: 99%

Expression of the MutL Homologue hMLH3 in Human Cells and its Role in DNA Mismatch Repair

et al. 2005

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The human mismatch repair (MMR) proteins hMLH1 and hPMS2 function in MMR as a heterodimer. Cells lacking either protein have a strong mutator phenotype and display microsatellite instability, yet mutations in the hMLH1 gene account for f50% of hereditary nonpolyposis colon cancer families, whereas hPMS2 mutations are substantially less frequent and less penetrant. Similarly, in the mouse model, Mlh1

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“…The yeast Msh2-Msh3 complex facilitates removal of nonhomologous ends that are formed during gene conversion (Sugawara et al, 1997) or during repair by the single-strand annealing pathway. A role for the Msh2 protein in the suppression of recombination between divergent sequences has also been reported both in yeast and mammalian cells (Chen and Jinks-Robertson, 1999;Ciotta et al, 1998;de Wind et al, 1995;Worth et al, 1994;Zhang et al, 2000).…”

Section: Introductionmentioning

confidence: 85%

The mammalian mismatch repair protein MSH2 is required for correct MRE11 and RAD51 relocalization and for efficient cell cycle arrest induced by ionizing radiation in G2 phase

et al. 2003

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In yeast, MSH2 plays an important role in mismatch repair (MMR) and recombination, whereas the function of the mammalian MSH2 protein in recombinational repair is not completely established. We examined the cellular responses of MSH2-deficient mouse cells to X-rays to clarify the role of MSH2 in recombinational repair. Cell survival, checkpoint functions and relocalization of the recombination-related proteins MRE11 and RAD51 were analysed in embryonic fibroblasts derived from MSH2 +/+ and MSH2 À/À mice, and in MSH2-proficient and deficient mouse colorectal carcinoma cells. Loss of MSH2 function was found to be associated with reduction in cell survival following radiation, absence of either MRE11 or RAD51 relocalization and a higher level of X-ray-induced chromosomal damage specifically in G2-phase cells. Finally, MSH2 À/À cells showed an inefficient early G2/M checkpoint, being arrested only transiently after irradiation before progressing into mitosis. Consistent with the premature release from the G2-phase arrest, activation of CHK1 was transient and CHK2 was not phosphorylated in synchronized MSH2-null cells. Our data suggest that an active MSH2 is required for a correct response to ionizing radiation-induced DNA damage in the G2 phase of the cell cycle, possibly connecting DSB repair to checkpoint signalling.

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Increased somatic recombination in methylation tolerant human cells with defective DNA mismatch repair

Cited by 39 publications

References 63 publications

Functional interactions and signaling properties of mammalian DNA mismatch repair proteins

Functional interactions and signaling properties of mammalian DNA mismatch repair proteins

Expression of the MutL Homologue hMLH3 in Human Cells and its Role in DNA Mismatch Repair

The mammalian mismatch repair protein MSH2 is required for correct MRE11 and RAD51 relocalization and for efficient cell cycle arrest induced by ionizing radiation in G2 phase

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