The secret life of Bcl-2: Apoptosis-independent inhibition of DNA repair by Bcl-2 family members

Abstract

Programmed cell death and DNA repair are two fundamental biological processes that play essential roles in cell fate and genetic transmission. The canonical role of Bcl-2 family members is the regulation of programmed cell death. Strikingly, numerous studies from different laboratories have shown that although Bcl-2 increases cell survival, it also inhibits all DNA repair systems, resulting in genome instability/variability. Bcl-2 affects the mechanistically distinct DNA repair systems via different mechanisms. These effects are generally independent of the regulation of apoptosis, revealing additional roles for Bcl-2. The targets of Bcl-2 include APE1, MSH2, PARP1, Ku70 and the oncosuppressor BRCA1. Targetting BRCA1 should be of particular importance because this might impact many essential cellular processes in which BRCA1 is involved, including homologous recombination (HR), non-homologous end joining (NHEJ), base excision repair, cell-cycle regulation, cell death, ubiquitination, inactivation of the X-chromosome, transcription, and protein translation. Beside the pathological consequences, inhibition of DNA repair by Bcl-2 can be, in contrast, advantageously used in some physiological situations: (1) repression of excessive unschedule HR, thus protecting against the accumulation of toxic HR intermediates and HR-dependent genome rearrangements; (2) inhibition of NHEJ might protect against retrovirus integration; (3) it has been proposed that inhibition of mismatch repair might also favors hypermutation at immunoglobulin genes. Finally, because Bcl-2 affects the maintenance of genome stability, one can suggest Bcl-2 might play a role in molecular evolution. Bcl-2 family members control cell death through complex stochiometric equilibriums. Incorporating DNA repair proteins to such an elaborate network should allow for a fine tuning of the coordinated control of cell viability and genetic stability/instability. Relationships between DNA repair and regulation of cell death represent exciting challenges for future prospects and are essential for the development of promising new strategies against cancer.