Blm-s, a BH3-Only Protein Enriched in Postmitotic Immature Neurons, Is Transcriptionally Upregulated by p53 during DNA Damage

Abstract

Summary: Programmed cell death is a pivotal process that regulates neuronal number during development. Key regulators of this process are members of the BCL-2 family. Using mRNA differential display, we identified a Bcl-2 family gene, Blm-s (Bcl-2-like molecule, short form), enriched in postmitotic neurons of the developing cerebral cortex. BLM-s functions as a BH3-only apoptosis sensitizer/derepressor and causes BAX-dependent mitochondria-mediated apoptosis by selectively binding to prosurvival BCL-2 or MCL-1. When challenged with γ-irradiation that produces DNA double-strand breaks (DSBs), Blm-s is transcriptionally upregulated in postmitotic immature neurons with concurrently increased apoptosis. RNAi-mediated depletion of Blm-s protects immature neurons from irradiation-induced apoptosis. Furthermore, Blm-s is a direct target gene of p53 and AP1 via the ataxia telangiectasia mutated (ATM)- and c-Jun N-terminal kinase (JNK)-signaling pathways activated by DSBs. Thus, BLM-s is likely an apoptosis sensor activated by DSBs accumulating in postmitotic immature neurons. : Liu et al. describe a Bcl-2 family gene, Blm-s, that is specifically expressed in postmitotic immature neurons during embryonic development. When the developing brain is challenged with γ-irradiation that produces DNA double-strand breaks (DBSs), Blm-s is upregulated in the neurons that undergo cell death. Depletion of Blm-s prevents immature neurons from irradiation-induced death. The authors also show that Blm-s is a direct target of p53 and AP1 via the signaling pathways activated by DSBs.