Masashi Narita scientific summary

Cellular senescence and tumour suppressor

Previous and current research

Replicative exhaustion of human diploid fibroblasts (HDFs) in culture causes an 'irreversible' cell-cycle arrest known as cellular senescence (replicative senescence). Young cells can also enter a similar state of cell-cycle arrest (premature senescence) in response to a variety of stimuli, such as expression of certain mitogenic oncogenes, oxidative stress, or DNA damage. Cellular senescence has been linked to tumour suppression and aging, and involves the activation of the p53 and p16INK4A/Rb tumour suppressor pathways, which are commonly mutated in tumours. Interestingly, senescence-inducing stimuli can also induce apoptosis in some cell types, such as immortalised or tumour cells. Cells appear to 'choose' between these two important tumour suppressor machineries, death or senescence, depending on the cellular context.

Despite increasing attention, the molecular basis of the senescence process is poorly understood. Unlike apoptosis, the senescence phenotype accumulates progressively and is established over multiple cell divisions, suggesting an involvement of epigenetic machinery. Furthermore, we have found that senescent cells exhibit distinct changes in chromatin structure, termed senescence associated heterochromatic foci (SAHFs), which are closely correlated with the stability of this phenotype. Based on these observations, we reason that chromatin alterations may underlie the 'irreversibility' of senescence. Our goal is to gain insights into tumour suppressor mechanisms through understanding the interplay between chromatin biology and the senescence phenotype. To achieve this goal, we combine stable RNAi genetics, cell biology, and biochemistry approaches.

Future projects

  • To identify the molecular mechanism of the stability of cell cycle arrest during cellular senescence.
  • To understand the relevance of heterochromatin and chromatin architecture in cellular senescence.
  • To identify new biomarkers of senescence and apply them to the clinical samples.
  • To characterise the chromatin protein profile in senescence and identify its significance in tumour suppression.
  • To understand the molecular basis of the relationship between cellular senescence and aging.