Tampering of Viruses and Bacteria with Host DNA Repair: Implications for Cellular Transformation

Abstract

A reduced ability to properly repair DNA is linked to a variety of human diseases, which in almost all cases is associated with an increased probability of the development of cellular transformation and cancer. DNA damage, that ultimately can lead to mutations and genomic instability, is due to many factors, such as oxidative stress, metabolic disorders, viral and microbial pathogens, excess cellular proliferation and chemical factors. In this review, we examine the evidence connecting DNA damage and the mechanisms that viruses and bacteria have evolved to hamper the pathways dedicated to maintaining the integrity of genetic information, thus affecting the ability of their hosts to repair the damage(s). Uncovering new links between these important aspects of cancer biology might lead to the development of new targeted therapies in DNA-repair deficient cancers and improving the efficacy of existing therapies. Here we provide a comprehensive summary detailing the major mechanisms that viruses and bacteria associated with cancer employ to interfere with mechanisms of DNA repair. Comparing these mechanisms could ultimately help provide a common framework to better understand how certain microorganisms are involved in cellular transformation.

Characterization of the interactome profiling of Mycoplasma fermentans DnaK in cancer cells reveals interference with key cellular pathways

“…Overall, the role of Mycoplasma fermentans in human diseases, including cancer, has been highlighted by several studies, and this research, together with other previous data ( Benedetti et al, 2020b , Benedetti et al, 2021 ), strongly indicate that this bacterium and others expressing DnaKs similar in amino acid composition and structure may play a more complex role beyond the one of being simple opportunistic bacteria. Given the close interactions between bacteria and host cells in the local microenvironment ( Maman and Witz, 2018 ), these data should help provide the foundation for future mechanistic studies on how bacteria interfere with essential cellular processes.…”

Pathogenicity and virulence of Hepatitis B virus

“…HBx also transcriptionally suppresses the expression of two other subunits of TFIIH, XPB (p89) and XPD (p80), through the interaction with the Sp1 TF[ 275 ]. Collectively, the association of HBx with the DNA repair machinery induces DNA damage in infected cells[ 276 ], implicating a role of HBx in hepatocarcinogenesis (for further details, see the previous review[ 277 ]).…”

Human papillomavirus-mediated carcinogenesis and tumor progression

“…The HPV replication cycle relies on the DNA Damage Response (DDR; reviewed in Blackford & Jackson, 2017) for crucial phases of virus genome amplification, early and late gene expression and virus production (reviewed in Spriggs & Laimins, 2017) and many molecular mechanisms of these interactions have been elucidated. For example, viral genome amplification in the suprabasal layers requires the activation of the ATM pathway; E7 binds to ATM through its LXCXE motif, thereby promoting CHK2 activation and activation of caspase needed for proper cleavage and activation of the E1 replication protein; HPV16E1/E2 mediate viral DNA replication in the presence of etoposide, which activates both the ATM and ATR pathways; HPV E1 and E2 co-localize with many components of the DDR pathway at integrated HPV18 genome replication centers (reviewed in Benedetti et al 2021).…”