Genomic Instability and DNA Damage Repair Pathways Induced by Human Papillomaviruses

Human papillomaviruses (HPV) are the causative agents of cervical and other anogenital cancers as well as those of the oropharynx. HPV proteins activate host DNA damage repair factors to promote their viral life cycle in stratified epithelia. Activation of both the ATR pathway and the ATM pathway are essential for viral replication and differentiation-dependent genome amplification. These pathways are also important for maintaining host genomic integrity and their dysregulation or mutation is often seen in human cancers. The APOBEC3 family of cytidine deaminases are innate immune factors that are increased in HPV positive cells leading to the accumulation of TpC mutations in cellular DNAs that contribute to malignant progression. The activation of DNA damage repair factors may corelate with expression of APOBEC3 in HPV positive cells. These pathways may actively drive tumor development implicating/suggesting DNA damage repair factors and APOBEC3 as possible therapeutic targets.

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Regulation of the Human Papillomavirus Life Cycle by DNA Damage Repair Pathways and Epigenetic Factors

Viruses ◽

10.3390/v12070744 ◽

2020 ◽

Vol 12 (7) ◽

pp. 744

Author(s):

Ekaterina Albert ◽

Laimonis Laimins

Keyword(s):

Dna Damage ◽

Life Cycle ◽

Dna Damage Repair ◽

Life Cycles ◽

Human Papillomaviruses ◽

Viral Transcription ◽

Productive Life ◽

Damage Repair ◽

Causative Agents ◽

Repair Pathways

Human papillomaviruses are the causative agents of cervical and other anogenital cancers along with approximately 60% of oropharyngeal cancers. These small double-stranded DNA viruses infect stratified epithelia and link their productive life cycles to differentiation. HPV proteins target cellular factors, such as those involved in DNA damage repair, as well as epigenetic control of host and viral transcription to regulate the productive life cycle. HPVs constitutively activate the ATM and ATR DNA repair pathways and preferentially recruit these proteins to viral genomes to facilitate productive viral replication. In addition, the sirtuin deacetylases along with histone acetyltransferases, including Tip60, are targeted in HPV infections to regulate viral transcription and replication. These pathways provide potential targets for drug therapy to treat HPV-induced disease.

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Human Papillomaviruses Target the DNA Damage Repair and Innate Immune Response Pathways to Allow for Persistent Infection

Viruses ◽

10.3390/v13071390 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1390

Author(s):

Elona Gusho ◽

Laimonis Laimins

Keyword(s):

Immune Response ◽

Dna Damage ◽

High Risk ◽

Persistent Infection ◽

Ataxia Telangiectasia ◽

Dna Damage Repair ◽

Immune Surveillance ◽

Human Papillomaviruses ◽

Innate Immune ◽

Damage Repair

Persistent infection with high-risk human papillomaviruses (HPVs) is the major risk factor associated with development of anogenital and oropharyngeal cancers. Initial infection by HPVs occurs into basal epithelial cells where viral genomes are established as nuclear episomes and persist until cleared by the immune response. Productive replication or amplification occurs upon differentiation and is dependent upon activation of the ataxia-telangiectasia mutated (ATM), ataxia telangiectasia and RAD3-related (ATR) DNA damage repair (DDR) pathways. In addition to activating DDR pathways, HPVs must escape innate immune surveillance mechanisms by antagonizing sensors, adaptors, interferons and antiviral gene expression. Both DDR and innate immune pathways are key host mechanisms that crosstalk with each other to maintain homeostasis of cells persistently infected with HPVs. Interestingly, it is still not fully understood why some HPV infections get cleared while others do not. Targeting of these two processes with antiviral therapies may provide opportunities for treatment of cancers caused by high-risk HPVs.

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DNA damage repair machinery and HIV escape from innate immune sensing

Frontiers in Microbiology ◽

10.3389/fmicb.2014.00176 ◽

2014 ◽

Vol 5 ◽

Cited By ~ 12

Author(s):

Christelle BrÃ©gnard ◽

Monsef Benkirane ◽

Nadine Laguette

Keyword(s):

Dna Damage ◽

Dna Damage Repair ◽

Innate Immune ◽

Damage Repair ◽

Immune Sensing ◽

Innate Immune Sensing

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p38MAPK and MK2 Pathways Are Important for the Differentiation-Dependent Human Papillomavirus Life Cycle

Journal of Virology ◽

10.1128/jvi.02712-14 ◽

2014 ◽

Vol 89 (3) ◽

pp. 1919-1924 ◽

Cited By ~ 13

Author(s):

Ayano Satsuka ◽

Kavi Mehta ◽

Laimonis Laimins

Keyword(s):

Dna Damage ◽

Human Papillomavirus ◽

Life Cycle ◽

Dna Damage Repair ◽

Human Papillomaviruses ◽

Genome Amplification ◽

Damage Repair ◽

In Cells

Amplification of human papillomaviruses (HPV) is dependent on the ATM DNA damage pathway. In cells with impaired p53 activity, DNA damage repair requires the activation of p38MAPK along with MAPKAP kinase 2 (MK2). In HPV-positive cells, phosphorylation of p38 and MK2 proteins was induced along with relocalization to the cytoplasm. Treatment with MK2 or p38 inhibitors blocked HPV genome amplification, identifying the p38/MK2 pathway as a key regulator of the HPV life cycle.

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DNA Damage Repair in Brain Tumor Immunotherapy

Frontiers in Immunology ◽

10.3389/fimmu.2021.829268 ◽

2022 ◽

Vol 12 ◽

Author(s):

Shihong Zhao ◽

Boya Xu ◽

Wenbin Ma ◽

Hao Chen ◽

Chuanlu Jiang ◽

...

Keyword(s):

Dna Damage ◽

Brain Tumors ◽

Dna Damage Repair ◽

Tumor Development ◽

Clinical Work ◽

Repair Process ◽

Damage Repair ◽

Rational Combination ◽

Repair Mechanisms ◽

Harsh Conditions

With the gradual understanding of tumor development, many tumor therapies have been invented and applied in clinical work, and immunotherapy has been widely concerned as an emerging hot topic in the last decade. It is worth noting that immunotherapy is nowadays applied under too harsh conditions, and many tumors are defined as “cold tumors” that are not sensitive to immunotherapy, and brain tumors are typical of them. However, there is much evidence that suggests a link between DNA damage repair mechanisms and immunotherapy. This may be a breakthrough for the application of immunotherapy in brain tumors. Therefore, in this review, first, we will describe the common pathways of DNA damage repair. Second, we will focus on immunotherapy and analyze the mechanisms of DNA damage repair involved in the immune process. Third, we will review biomarkers that have been or may be used to evaluate immunotherapy for brain tumors, such as TAMs, RPA, and other molecules that may provide a precursor assessment for the rational implementation of immunotherapy for brain tumors. Finally, we will discuss the rational combination of immunotherapy with other therapeutic approaches that have an impact on the DNA damage repair process in order to open new pathways for the application of immunotherapy in brain tumors, to maximize the effect of immunotherapy on DNA damage repair mechanisms, and to provide ideas and guidance for immunotherapy in brain tumors.

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