Senescence in RASopathies, a possible novel contributor to a complex pathophenoype.

Engler, Melanie; Fidan, Miray; Nandi, Sayantan; Cirstea, Ion Cristian

Senescence is a biological process that induces a permanent cell cycle arrest and a specific gene expression program in response to various stressors. Following studies over the last few decades, the concept of senescence has evolved from an antiproliferative mechanism in cancer (oncogene-induced senescence) to a critical component of physiological processes associated with embryonic development, tissue regeneration, ageing and its associated diseases. In somatic cells, oncogenic mutations in RAS-MAPK pathway genes are associated with oncogene-induced senescence and cancer, while germline mutations in the same pathway are linked to a group of monogenic developmental disorders generally termed RASopathies. Here, we consider that in these disorders, senescence induction may result in opposing outcomes, a tumour protective effect and a possible contributor to a premature ageing phenotype identified in Costello syndrome, which belongs to the RASopathy group. In this review, we will highlight the role of senescence in organismal homeostasis and we will describe the current knowledge about senescence in RASopathies. Additionally, we provide a perspective on examples of experimentally characterised RASopathy mutations that, alone or in combination with various stressors, may also trigger an age-dependent chronic senescence, possibly contributing to the age-dependent worsening of RASopathy pathophenotype and the reduction of lifespan.