The high-mobility group A (HMGA) proteins are non-histone chromatin proteins that are most well known as transcriptional activators and as proliferogenic and tumorigenic agents. Scott Lowe and colleagues now identify a surprising new role for HMGA proteins as promoters of cellular senescence.

Senescence is a growth-arrest programme that prevents uncontrolled cellular proliferation and that is thought to counteract tumour formation. Senescent cells have a typical appearance in which heterochromatin accumulates in nuclear bodies that are known as senescence-associated heterochromatic foci (SAHF). These foci are thought to represent repressive chromatin environments that prevent the activation of proliferogenic genes.

Lowe and colleagues analysed the chromatin composition of senescent fibroblasts and found that HMGA1 and HMGA2 associate with the chromatin fraction of these cells. Unexpectedly, HMGA proteins are enriched at SAHF, and ectopic expression of HMGA1 or HMGA2 in cycling fibroblasts promoted cell-cycle arrest and the accumulation of SAHF-like foci. Further studies showed that these proteins cooperate with the tumour suppressor p16INK4a to promote SAHF formation and proliferative arrest. On the other hand, disruption of HMGA function by competitive DNA-binding assays or by the knockdown of HMGA1 or HMGA2 resulted in the disappearance of SAHF, confirming that these proteins are integral structural components of these heterochromatic domains.

In normal cells, HMGA proteins are renowned gene activators that bind to DNA and create a transcriptionally permissive 'open' chromatin environment. So, it is reasonable to assume that they might promote senescence by activating senescence-associated genes. In fact, microarray experiments indicated that, in senescent fibroblasts, HMGA proteins function as transcriptional repressors, downregulating proliferation-associated genes such as the E2F target genes CDC2 and cyclin A. Taken together with their predilection for SAHF, these data indicate that, during senescence, HMGA proteins limit transcription by chromatin-mediated repression.

These findings indicate that the function of HMGA proteins is modulated, and the authors point out that this modulation might resemble that of histone proteins. HMGA proteins, similar to histones, are subject to post-translational modifications such as acetylation, phosphorylation and methylation, and opposing HMGA functions might be determined by the specific patterns of these modifications. The revelation that HMGA1 and HMGA2 have a putative role in tumour suppression as well as in oncogenesis highlights the importance of considering cellular context when analysing the roles of proteins, and provides important insights into the complex machinery that orchestrates senescence.