In Brief

Apoptosis

Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis. Boehning, D. et al. Nature Cell Biol. 9 Nov 2003 (DOI: 10.1038/ncb1063)

That small concentrations of Ca²⁺ can inhibit inositol-1,4,5-trisphosphate receptor (Ins(1,4,5)P₃R) function is a well-known feedback mechanism to prevent excess Ca²⁺ release. Boehning and colleagues now show that physiological quantities of cytochrome c can block this Ca²⁺-mediated inhibition of Ins(1,4,5)P₃R function. Early in apoptosis, cytochrome c released from mitochondria translocates to the endoplasmic reticulum and binds Ins(1,4,5)P₃R. This sensitizes Ins(1,4,5)P₃R to increased Ca²⁺ release, causing a large cytochrome c release that amplifies the apoptotic signal.

Telomeres

DNA damage foci at dysfunctional telomeres. Takai, H. et al. Curr. Biol. 13, 1549–1556 (2003)

A DNA damage checkpoint response in telomere-initiated senescence. d'Adda di Fagagna, F. et al. Nature 5 Nov 2003 (DOI: 10.1038/nature02118)

The groups of de Lange and Jackson now show that dysfunctional telomeres activate a DNA-damage-checkpoint response. de Lange and colleagues uncapped telomeres by inhibiting the duplex TTAGGG repeat binding factor (TRF2), which is essential for telomere protection. Known DNA-damage-response factors, including 53BP1, γ-H2AX, Rad17, ATM and Mre11, became associated with the uncapped dysfunctional telomeres at 'telomere dysfunction-induced foci' (TIFs). And inhibiting the upstream protein kinase activators of the DNA-damage checkpoint reduced the accumulation of 53BP1. Using human diploid fibroblast (HDF) cell lines that undergo senescence as a result of telomere shortening, Jackson and colleagues detected a 'senescence-associated DNA damage focus' (SDF) of γ-H2AX colocalized with 53BP1, MDC1, NBS1 and SMC1 pS966. This telomere-initiated senescence triggers a complete DNA-damage response — dysfunctional telomeres contribute directly to this response. Accumulation of the DNA-damage-response factors was also seen when TRF2 was inhibited in immortalized human fibroblasts.

Protein assembly

An essential role of Sam50 in the protein sorting and assembly machinery of the mitochondrial outer membrane. Kozjak, V. et al. J. Biol. Chem. 15 Oct 2003 [epub ahead of print]

Kozjak and colleagues report the identification of Sam50, which associates with Mas37 to form the Saccharomyces cerevisiae mitochondrial outer membrane sorting and assembly machinery (SAM complex). Using an in organello assembly assay, Sam50 was shown to be crucial for the assembly of β-barrel proteins of the outer membrane, such as Tom40 and porin. In addition, Sam50 is only the second mitochondrial outer membrane protein that is known to be essential for cell viability.