ATM Kinase-Dependent Regulation of Autophagy: A Key Player in Senescence?

Increasing evidence suggests a strong interplay between autophagy and genomic
stability. Recently, several papers have demonstrated a molecular connection between
the DNA Damage Response (DDR) and autophagy and have explored how this link
influences cell fate and the choice between apoptosis and senescence in response to
different stimuli. The aberrant deregulation of this interplay is linked to the development
of pathologies, including cancer and neurodegeneration. Ataxia-telangiectasia mutated
kinase (ATM) is the product of a gene that is lost in Ataxia-Telangiectasia (A-T),
a rare genetic disorder characterized by ataxia and cerebellar neurodegeneration,
defects in the immune response, higher incidence of lymphoma development, and
premature aging. Importantly, ATM kinase plays a central role in the DDR, and it can
finely tune the balance between senescence and apoptosis: activated ATM promotes
autophagy and in particular sustains the lysosomal-mitochondrial axis, which in turn
promotes senescence and inhibits apoptosis. Therefore, ATM is the key factor that
enables cells to escape apoptosis by entering senescence through modulation of
autophagy. Importantly, unlike apoptotic cells, senescent cells are viable and have the
ability to secrete proinflammatory and mitogenic factors, thus influencing the cellular
environment. In this review we aim to summarize recent advances in the understanding
of molecular mechanisms linking DDR and autophagy to senescence, pointing out the
role of ATM kinase in these cellular responses. The significance of this regulation in the
pathogenesis of Ataxia-Telangiectasia will be discussed.