Impact of the DNA Damage Response on Human Papillomavirus Chromatin

Gautam, Dipendra; Moody, Cary A.

doi:10.1371/journal.ppat.1005613

Cited by 27 publications

(23 citation statements)

References 41 publications

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“…An example of a growth factor-stimulated STAT is STAT5. DNA damage signaling is critical for the amplification of viral genomes and completion of the viral life cycle (Moody and Laimins 2009; Gautam and Moody 2016). Cells containing HPV31 genomes have high levels of total and phosphorylated (activated) STAT5 even in the absence of exogenous growth factors (Hong and Laimins 2013).…”

Section: Transcription Factors Regulated By E7mentioning

confidence: 99%

“…In cooperation with E6, E7 increases Sirt1 levels through the C terminus and LXCXE motifs (Allison, Jiang et al 2009; Langsfeld, Bodily et al 2015). Sirt1 binds to the viral genome and recruits homologous recombination factors which are important for episomal maintenance, amplification, and late gene expression (Langsfeld, Bodily et al 2015; Gautam and Moody 2016). Sirt1 levels may also drive changes in cellular gene expression but this is as yet unknown.…”

Section: Other Promoters Regulated By E7mentioning

confidence: 99%

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The human papillomavirus E7 oncoprotein as a regulator of transcription

2017

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High-risk human papillomaviruses (HPVs) encode oncoproteins which manipulate gene expression patterns in the host keratinocytes to facilitate viral replication, regulate viral transcription, and promote immune evasion and persistence. In some cases, oncoprotein-induced changes in host cell behavior can cause progression to cancer, but a complete picture of the functions of the viral oncoproteins in the productive HPV life cycle remains elusive. E7 is the HPV-encoded factor most responsible for maintaining cell cycle competence in differentiating keratinocytes. Through interactions with dozens of host factors, E7 has an enormous impact on host gene expression patterns. In this review, we will examine the role of E7 specifically as a regulator of transcription. We will discuss mechanisms of regulation of cell cycle-related genes by E7 as well as genes involved in immune regulation, growth factor signaling, DNA damage responses, microRNAs, and others pathways. We will also discuss some unanswered questions about how transcriptional regulation by E7 impacts the biology of HPV in both benign and malignant conditions.

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Section: Transcription Factors Regulated By E7mentioning

confidence: 99%

Section: Other Promoters Regulated By E7mentioning

confidence: 99%

The human papillomavirus E7 oncoprotein as a regulator of transcription

2017

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“…Gillespie at al demonstrated that γH2AX is bound to HPV genomes (94), which may be important in facilitating the recruitment of downstream DDR factors to HPV genomes (96). The finding that Rad51 and BRCA1 localize to sites of viral DNA synthesis suggests that HPV may utilize ATM activity to drive productive replication in a recombination-dependent manner.…”

Section: Hpv Manipulation Of the Dna Damage Response Pathwaysmentioning

confidence: 99%

“…The binding of Rad51, as well as NBS1 to HPV DNA is dependent on the deacetylase Sirtuin 1 (SIRT1), which is upregulated in HPV positive cells and required for productive viral replication (97, 98). SIRT1, as well as TIP60 both influence the DSB repair pathway of choice to HR through modification of cellular chromatin (99, 100), and may provide a similar role in HPV positive cells through effects on viral chromatin (96). As mentioned previously, BRCA1 also influences repair pathway choice to HR by promoting end resection (68).…”

Section: Hpv Manipulation Of the Dna Damage Response Pathwaysmentioning

confidence: 99%

Modulation of the DNA damage response during the life cycle of human papillomaviruses

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Moody

2017

Virus Research

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Human papillomavirus (HPV) is the most common sexually transmitted viral infection. Infection with certain types of HPV pose a major public health risk as these types are associated with multiple human cancers, including cervical cancer, other anogenital malignancies and an increasing number of head and neck cancers. The HPV life cycle is closely tied to host cell differentiation with late viral events such as structural gene expression and viral genome amplification taking place in the upper layers of the stratified epithelium. The DNA damage response (DDR) is an elaborate signaling network of proteins that regulate the fidelity of replication by detecting, signaling and repairing DNA lesions. ATM and ATR are two kinases that are major regulators of DNA damage detection and repair. A multitude of studies indicate that activation of the ATM (Ataxia telangiectasia mutated) and ATR (Ataxia telangiectasia and Rad3-related) pathways are critical for HPV to productively replicate. This review outlines how HPV interfaces with the ATM- and ATR-dependent DNA damage responses throughout the viral life cycle to create an environment supportive of viral replication and how activation of these pathways could impact genomic stability.

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“…The mode of replication is again dependent on E1 and E2 (Egawa et al, 2012; Ozbun and Meyers, 1998), and amplifies viral DNA to high copy number. E1 and E7 independently promote a DNA damage response (DDR) that recruits factors that the virus can hijack to replicate its DNA outwith S-phase (Gautam and Moody, 2016; McKinney et al, 2015). During this phase, there is sustained synthesis of intermediate (E1, E2 and E4) and late (L1 and L2) transcripts.…”

Section: Hpv Infectious Cyclementioning

confidence: 99%

Host cell restriction factors that limit transcription and replication of human papillomavirus

et al. 2017

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The life cycle of human papillomaviruses (HPV) is tightly regulated by the differentiation state of mucosal and cutaneous keratinocytes. To counteract viral infection, constitutively expressed cellular factors, which are defined herein as restriction factors, directly mitigate viral gene expression and replication. In turn, some HPV gene products target these restriction factors and abrogate their anti-viral effects to establish efficient gene expression and replication programs. Ironically, in certain circumstances, this delicate counterbalance between viral gene products and restriction factors facilitates persistent infection by HPVs. This review serves to recapitulate the current knowledge of nuclear restriction factors that directly affect the HPV infectious cycle.

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Impact of the DNA Damage Response on Human Papillomavirus Chromatin

Cited by 27 publications

References 41 publications

The human papillomavirus E7 oncoprotein as a regulator of transcription

The human papillomavirus E7 oncoprotein as a regulator of transcription

Modulation of the DNA damage response during the life cycle of human papillomaviruses

Host cell restriction factors that limit transcription and replication of human papillomavirus

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