The sirtuins are a family of proteins named (somewhat unfortunately, in my opinion) after their founding and first-described member, the yeast histone deacetylase SIR2. In mammals, there are seven family members, SIRT1-7. Over the past few years, characterizing the function of each protein in every tissue it happens to be expressed has become something of a cottage industry: at the Cold Spring Harbor aging conference last fall, easily 25% of the talks were sirtuin-related.
This happens to be Sirt2’s week in the sun, with two independent studies revealing the protein’s role in regulating the cell cycle and differentation of the glial cells where it is expressed.
Inoue et al. show that Sirt2 is responsible for a novel mitotic checkpoint, acting prior to the well-characterized spindle-pole checkpoints that can be induced by microtubule destabilization. The protein’s activity appears to be regulated by nuclear-cytoplasmic shuttling. Nuclear export of Sirt2 is blocked under conditions that might cause mitotic stress, implying the existence of a factor that recognizes this stress and modifies either Sirt2 or the export machinery in response:
SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress
… We herein investigated whether SIRT2 functions in the mitotic checkpoint in response to mitotic stress caused by microtubule poisons. By monitoring chromosome condensation, the exogenously expressed SIRT2 was found to block the entry to chromosome condensation and subsequent hyperploid cell formation in glioma cell lines with a persistence of the cyclin B/cdc2 activity in response to mitotic stress. SIRT2 is thus a novel mitotic checkpoint protein that functions in the early metaphase to prevent chromosomal instability (CIN), characteristics previously reported for the CHFR protein. … Although SIRT2 is normally exclusively located in the cytoplasm, the rapid accumulation of SIRT2 in the nucleus was observed after treatment with a nuclear export inhibitor, leptomycin B and ionizing radiation in normal human fibroblasts, suggesting that nucleo-cytoplasmic shuttling regulates the SIRT2 function. Collectively, our results suggest that the further study of SIRT2 may thus provide new insights into the relationships among CIN, epigenetic regulation and tumorigenesis.
This study was performed in glioma cell lines, which (as cancers do) divide rapidly; in contrast, normal glia have lost their capacity to proliferate. Does Sirt2 has a function in these non-dividing cells as well? Li et al. argue that the protein acts primarily by deacetylating α-tubulin (remember, the founding member of the family is a histone deacetylase, and most family members have retained some sort of protein deacetylation activity), and thereby limits the progress of glial differentiation:
Sirtuin 2, a Mammalian Homolog of Yeast Silent Information Regulator-2 Longevity Regulator, Is an Oligodendroglial Protein That Decelerates Cell Differentiation through Deacetylating α-Tubulin
… Here, we show that sirtuin 2 (SIRT2), a mammalian SIR2 homolog, is an oligodendroglial cytoplasmic protein and localized to the outer and juxtanodal loops in the myelin sheath. Among cytoplasmic proteins of OLN-93 oligodendrocytes, α-tubulin was the main substrate of SIRT2 deacetylase. In cultured primary oligodendrocyte precursors (OLPs), SIRT2 emergence accompanied elevated α-tubulin acetylation and OLP differentiation into the prematurity stage. Small interfering RNA knockdown of SIRT2 increased the α-tubulin acetylation, myelin basic protein expression, and cell arbor complexity of OLPs. SIRT2 overexpression had the opposite effects, and counteracted the cell arborization-promoting effect of overexpressed juxtanodin. SIRT2 mutation concomitantly reduced its deacetylase activity and its impeding effect on OLP arborization. These results demonstrated a counterbalancing role of SIRT2 against a facilitatory effect of tubulin acetylation on oligodendroglial differentiation. Selective SIRT2 availability to oligodendroglia may have important implications for myelinogenesis, myelin–axon interaction, and brain aging.
The two papers focus on different aspects of Sirt2 biology, but it’s tempting to speculate that the molecular mechanism of the pre-mitotic checkpoint in dividing glioma cells might have something to do with the α-tubulin deacetylase activity revealed in the study of differentiated, non-dividing glia. The mitotic spindle is composed of tubulin, after all.
Here is a model that relies only on the known biochemistry and cell biology of Sirt2, as described in these two papers: The checkpoint effector monitors the acetylation state of the free tubulin pool, and only allows mitosis to occur if the ratio of acetylated to deacetylated monomer is above some critical value. When Sirt2 is allowed to linger in the nucleus, as a result of conditions that would induce mitotic stress, it deacetylates α-tubulin and lowers the ratio, thereby triggering the checkpoint.