Bcl-2 expression suppresses mismatch repair activity through inhibition of E2F transcriptional activity

  title={Bcl-2 expression suppresses mismatch repair activity through inhibition of E2F transcriptional activity},
  author={Cha Kyung Youn and Hyun-Ju Cho and Soo-Hyun Kim and Hong-Beum Kim and Mi-hwa Kim and In Youb Chang and Jung-Sup Lee and Myung Hee Chung and Kyung-soo Hahm and Ho Jin You},
  journal={Nature Cell Biology},
Bcl-2 stimulates mutagenesis after the exposure of cells to DNA-damaging agents. However, the biological mechanisms of Bcl-2-mediated mutagenesis have remained largely obscure. Here we demonstrate that the Bcl-2-mediated suppression of hMSH2 expression results in a reduced cellular capacity to repair mismatches. The pathway linking Bcl-2 expression to the suppression of mismatch repair (MMR) activity involves the hypophosphorylation of pRb, and then the enhancement of the E2F–pRb complex. This… 
Bcl2 Suppresses DNA Repair by Enhancing c-Myc Transcriptional Activity*
Bcl2, in addition to its survival function, may also suppress DNA repair in a novel mechanism involving c-Myc and APE1, which may lead to an accumulation of DNA damage in living cells, genetic instability, and tumorigenesis.
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Anti-apoptotic Protein BCL2 Down-regulates DNA End Joining in Cancer Cells*
The results suggest that EJ in cancer cells could be negatively regulated by the anti-apoptotic protein, BCL2, and this may contribute toward increased chromosomal abnormalities in cancer.
Identification of an ataxia telangiectasia-mutated protein mediated surveillance system to regulate Bcl-2 overexpression
Evidence is provided suggesting that activation of ATM suppresses Bcl-2-induced tumorigenesis, and that attenuation of ATM function may be an important event in breast cancer progression, as well as indicating an ATM-mediated surveillance system for regulating B cl-2 overexpression.
A mismatched role for Bcl-2
This study has shown that by retaining E2F-1 in a transcriptionally inactive state, through the induction of hypophosphorylated retinoblastoma protein, Bcl-2 hinders the expression of a key component of mismatch repair, MSH2.
Bax and Bid, two proapoptotic Bcl-2 family members, inhibit homologous recombination, independently of apoptosis regulation
It is shown that the induction of both recombinant cells and recombinant colonies was impaired when expressing Bcl-2 family members, in hamster as well as in human cells, revealing a mechanism of HR downregulation by potentially proapoptotic proteins, distinct from and parallel to degradation of recombination proteins.
Senescence-Dependent MutSα Dysfunction Attenuates Mismatch Repair
Results indicate that the suppression of E2F1 transcriptional activity in senescence cells lead to stable repression of MSH2, followed by a induction of MutSα dysfunction, which results in a reduced cellular MMR capacity in senescent cells.


Bcl-2-induced changes in E2F regulatory complexes reveal the potential for integrated cell cycle and cell death functions.
A mechanism for cell cycle regulation by Bcl-2 that occurs at the level of E2F transcriptional activity is revealed, which may help to consolidate the cell survival and cell cycle effects of B cl-2 through a common transcriptional mechanism.
Inhibition of apoptosis by overexpressing Bcl-2 enhances gene amplification by a mechanism independent of aphidicolin pretreatment.
  • D. YinR. Schimke
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1996
Results are consistent with the concept that gene amplification occurs at a higher frequency during drug-induced cell cycle perturbation, and suggest that Bcl-2 evidently increases the number of selected amplified colonies by prolonging cell survival during the perturbations.
Nucleotide excision repair capacity is attenuated in human promyelocytic HL60 cells that overexpress BCL2.
The data suggest that Bcl2 may promote mutagenesis and genomic instability in surviving cells, and both BCL2-overexpressing and NAC-treated cells were more resistant to UV.
Cross talk between cell death and cell cycle progression: BCL-2 regulates NFAT-mediated activation.
Select genetic aberrations in the apoptotic pathway reveal a cell autonomous coregulation of activation, as well as a cysteine protease inhibitor that also blocks apoptosis.
A novel role for the Bcl‐2 protein family: specific suppression of the RAD51 recombination pathway
The Bcl‐2 gene combines two separable cancer‐prone phenotypes: apoptosis repression and a genetic instability/mutator phenotype, which could represent a mammalian version of the bacterial SOS repair system.
Suppression of apoptosis by Bcl-2 to enhance benzene metabolites-induced oxidative DNA damage and mutagenesis: A possible mechanism of carcinogenesis.
Results in this study provide a novel benzene-induced carcinogenesis mechanism by which up-regulation of Bcl-2 protein may promote the susceptibility to benzene metabolites-induced mutagenesis by overriding apoptosis and attenuating DNA repair capacity.
BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax
Results establish a functional role for the BH1 and BH2 domains and suggest Bcl-2 exerts its action through heterodimerization with Bax, yet still permitted B cl-2 homo-dimerization.
E2Fs up-regulate expression of genes involved in DNA replication, DNA repair and mitosis
The E2F family of transcription factors plays a pivotal role in the regulation of cell proliferation in higher eukaryotes and up-regulates the expression of genes not previously described as E1F target genes, which suggest that E 2F affects cell cycle progression both at S phase and during mitosis.
Bax alpha perturbs T cell development and affects cell cycle entry of T cells.
Data indicate that apoptotic regulatory proteins can modulate the level of cell cycle‐controlling proteins and thereby directly impact on the cell cycle.
Bcl-2 Retards Cell Cycle Entry through p27Kip1, pRB Relative p130, and Altered E2F Regulation
Bcl-2 appears to retard cell cycle entry by increasing p27 and p130 levels and maintaining repressive complexes of p130 with E2F4, perhaps to delay E2f1 expression.