BCL2 overexpression leads to inhibition of apoptosis, so promoting carcinogenesis. Now, Ho Jin You and colleagues show that BCL2 also stimulates mutagenesis through its independent function in cell-cycle arrest, by suppressing DNA repair.

The authors first investigated the effect of treatment with the alkylating agent MNNG on a cell line with inducible BCL2. When BCL2 expression was induced the cells were more resistant to MNNG-induced death than control cells, and spontaneous mutagenesis and mutagenesis caused by MNNG were also higher. Decrease of mismatch-repair (MMR) activity correlated with the degree of induction of BCL2. Cells expressing a BCL2 mutant that is unable to induce cell-cycle arrest were more resistant to MNNG mutation than either control cells or cells expressing an anti-apoptotic deficient BCL2 mutant. Moreover, only cells expressing the anti-apoptotic deficient BCL2 mutant had reduced MMR activity. This indicates that BCL2-induced cell-cycle arrest is important for the BCL2-mediated suppression of MMR, but that the anti-apoptotic function is not involved.

So how does BCL2 suppress MMR? The authors discovered that the mRNA of the MMR protein MSH2 was significantly decreased in cells after BCL2 induction. As MSH2 is an E2F-responsive gene, the authors investigated whether inactivation of this transcription factor could mediate the BCL2-induced suppression of MSH2. BCL2-expressing cells had more E2F1 bound to phosphorylated RB — which keeps E2F1 inactive — than when BCL2 expression was not induced, and binding of E2F1 to the MSH2 promoter was reduced. Moreover, when small interfering RNAs that target E2F1 were added to the cells, MSH2 espression and MMR activity were reduced in BCL2-expressing cells.

You and colleagues confirmed that the same mechanisms of MMR suppression occurred in two human B-cell lymphoma cell lines that overexpress BCL2, but not in another B-cell lymphoma cell line that does not express BCL2. These data indicate that far from cell-cycle arrest protecting cells from oncogenesis, it actually induces mutagenesis. These findings might help to explain why cancer incidence increases exponentially with the ageing process, in which senescent cells (with irreversible growth arrest) accumulate.