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Review
. 2023 Nov 1;20(1):250.
doi: 10.1186/s12985-023-02203-y.

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

Xinna Wu  1 , Xuqiang Zhou  2 , Sanying Wang  3 , Genxiang Mao  4   5
Affiliations
Review

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

Xinna Wu et al. Virol J. .

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).

Keywords: Cell cycle; Cellular senescence; DNA damage; Human cytomegalovirus; Senescence-associated secretory phenotype.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The DNA damage response. Responses to DNA damage caused by double-strand breaks (DSBs) and single-stranded DNA (ssDNA). The MRN complex detects DNA DSBs and signals them by activating ATM. The accumulation of ssDNA at stalled or stressed replication forks activates ATR. Following the activation of transducer kinases, DNA damage signaling is initiated, which includes DNA repair processes (lower panel) and cell cycle checkpoints (upper panel). Direct and indirect interactions are indicated by solid and dashed arrows, respectively. This figure was modified according to the published Fig. 1 in reference [203].
Fig. 2
Fig. 2
The relationship between cellular senescence and DNA damage. Senescence can be activated by different stimuli, including telomere shortening, DNA damage, oxidative stress, and oncogene activation. A central factor involved in all aspects of senescence is the sustained DNA damage response (DDR), which causes cell cycle arrest via the p53 and RB-dependent pathways and SASP secretion via the NF-kB and cGAS-STING pathways, ultimately inducing cellular senescence. This figure was modified according to the published Fig. 1 in reference [204].
Fig. 3
Fig. 3
cGAS is a key linkage between DNA damage and SASP. Exogenous and Endogenous aberrant DNA bind cyclic GMP-AMP synthase (cGAS) and activate the synthesis of 2′3′-cyclic GMP-AMP (2′3′-cGAMP), which binds to and induces oligomerization of STING (stimulator of interferon genes) in the endoplasmic reticulum and its incorporation into vesicles. When STING is activated, it attracts and activates TANK-binding kinase 1 (TBK1), which phosphorylates STING and the interferon regulatory factor IRF3, activating the NF-κB signaling cascade. The sensor kinase ataxia telangiectasia mutated (ATM) also activates TBK1, through the phosphorylation of NF-κB essential modulator (NEMO), a member of the IB kinase complex that activates NF-κB. In response to nuclear DNA damage, ATM can potentially activate STING in a non-canonical manner. PARP-1, poly (ADP-ribose) polymerase 1, is an essential DNA damage sensor. This figure was modified according to the published Fig. 3 in reference [202].
Fig. 4
Fig. 4
The model of HCMV-induced senescence. Human cytomegalovirus (HCMV) has two modes of infection: latent and productive. (A) In the latent infection, cells from the myeloid lineage are considered as primary sites. Long exposure to HCMV enables terminal differentiation of T cells leading to accumulation of exhausted CD28 T cells, which secrete TNF-α and IFN-γ to promote inflamm-aging. (B) In the productive infection, HCMV-infected cells show senescence phenotype, including cell cycle arrest and SASP.
Fig. 5
Fig. 5
Model of the host DNA damage response induced by HCMV infection. Efficient replication of HCMV requires DDR centered on ATM and E2F1. HCMV infection can activate multiple DDR proteins, including ATM and the downstream effector proteins p53 and H2AX. IE1, IE2, pp71, and pUL97 of HCMV can inactivate RB family members, leading to dysregulation of E2F1 proteins and subsequent production of DSBs.
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