DNA damage response(DDR): a link between cellular senescence and human cytomegalovirus

Abstract

The DNA damage response (DDR) is a signaling cascade that is triggered by DNA damage, involving the halting of cell cycle progression and repair. It is a key event leading to senescence, which is characterized by irreversible cell cycle arrest and the senescence-associated secretory phenotype (SASP) that includes the expression of inflammatory cytokines. Human cytomegalovirus (HCMV) is a ubiquitous pathogen that plays an important role in the senescence process. It has been established that DDR is necessary for HCMV to replicate effectively. This paper reviews the relationship between DDR, cellular senescence, and HCMV, providing new sights for virus-induced senescence (VIS).

The Molecular Mechanisms in Senescent Cells Induced by Natural Aging and Ionizing Radiation

“…One of the key factors that provokes NF-kB is DNA damage [ 140 ]. As mentioned earlier, failure to repair the damage results in the formation of a persistent DDR response characterized by cell cycle arrest, prolonged activation of ATR/ATM kinases, and SASP secretion through various pathways including NF-kB, ultimately leading to cellular senescence [ 141 ]. There is evidence reporting that ATM is a key activator of sustained NF-kB during DNA damage [ 142 ].…”

“…Persistent DDR correlates with IL-6 production, and ATM depletion reduces IL-6 levels by 70%, confirming the role of DDR in stimulating inflammatory cytokine secretion [ 161 ]. Wu et al [ 141 ] reported an inseparable link between DDR and cytomegalovirus (HCMV)-induced SASP production and cellular senescence. Prolonged exposure to latent infection with HCMV leads to T-cell terminal differentiation, resulting in the accumulation of exhausted CD28 T-cells that secrete TNF-α and IFN-γ, promoting inflammatory senescence.…”