Beta-Genus Human Papillomavirus 8 E6 Destabilizes the Host Genome by Promoting p300 Degradation

The beta genus of human papillomaviruses infects cutaneous keratinocytes. Their replication depends on actively proliferating cells and, thus, they conflict with the cellular response to the DNA damage frequently encountered by these cells. This review focus on one of these viruses (HPV8) that counters the cellular response to damaged DNA and mitotic errors by expressing a protein (HPV8 E6) that destabilizes a histone acetyltransferase, p300. The loss of p300 results in broad dysregulation of cell signaling that decreases genome stability. In addition to discussing phenotypes caused by p300 destabilization, the review contains a discussion of the extent to which E6 from other β-HPVs destabilizes p300, and provides a discussion on dissecting HPV8 E6 biology using mutants.

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The Yeast PCNA Unloader Elg1 RFC-Like Complex Plays a Role in Eliciting the DNA Damage Checkpoint

mBio ◽

10.1128/mbio.01159-19 ◽

2019 ◽

Vol 10 (3) ◽

Cited By ~ 3

Author(s):

Soumitra Sau ◽

Batia Liefshitz ◽

Martin Kupiec

Keyword(s):

Dna Damage ◽

Dna Replication ◽

Cellular Response ◽

Genome Stability ◽

Adaptor Proteins ◽

Nuclear Antigen ◽

Dna Damage Checkpoint ◽

Activation Process ◽

Checkpoint Activation ◽

Dna Replication And Repair

ABSTRACT The PCNA (proliferating cell nuclear antigen) ring plays central roles during DNA replication and repair. The yeast Elg1 RFC-like complex (RLC) is the principal unloader of chromatin-bound PCNA and thus plays a central role in maintaining genome stability. Here we identify a role for Elg1 in the unloading of PCNA during DNA damage. Using DNA damage checkpoint (DC)-inducible and replication checkpoint (RC)-inducible strains, we show that Elg1 is essential for eliciting the signal in the DC branch. In the absence of Elg1 activity, the Rad9 (53BP1) and Dpb11 (TopBP1) adaptor proteins are recruited but fail to be phosphorylated by Mec1 (ATR), resulting in a lack of checkpoint activation. The chromatin immunoprecipitation of PCNA at the Lac operator sites reveals that accumulated local PCNA influences the checkpoint activation process in elg1 mutants. Our data suggest that Elg1 participates in a mechanism that may coordinate PCNA unloading during DNA repair with DNA damage checkpoint induction. IMPORTANCE The Elg1protein forms an RFC-like complex in charge of unloading PCNA from chromatin during DNA replication and repair. Mutations in the ELG1 gene caused genomic instability in all organisms tested and cancer in mammals. Here we show that Elg1 plays a role in the induction of the DNA damage checkpoint, a cellular response to DNA damage. We show that this defect is due to a defect in the signal amplification process during induction. Thus, cells coordinate the cell's response and the PCNA unloading through the activity of Elg1.

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Control of genome stability by Slx protein complexes

Biochemical Society Transactions ◽

10.1042/bst0370495 ◽

2009 ◽

Vol 37 (3) ◽

pp. 495-510 ◽

Cited By ~ 26

Author(s):

John Rouse

Keyword(s):

Dna Damage ◽

Dna Replication ◽

Protein Interactions ◽

Cellular Response ◽

Genome Stability ◽

Molecular Mechanisms ◽

Excision Repair ◽

Protein Complexes ◽

Alkylating Agents ◽

Strand Break

The six Saccharomyces cerevisiae SLX genes were identified in a screen for factors required for the viability of cells lacking Sgs1, a member of the RecQ helicase family involved in processing stalled replisomes and in the maintenance of genome stability. The six SLX gene products form three distinct heterodimeric complexes, and all three have catalytic activity. Slx3–Slx2 (also known as Mus81–Mms4) and Slx1–Slx4 are both heterodimeric endonucleases with a marked specificity for branched replication fork-like DNA species, whereas Slx5–Slx8 is a SUMO (small ubiquitin-related modifier)-targeted E3 ubiquitin ligase. All three complexes play important, but distinct, roles in different aspects of the cellular response to DNA damage and perturbed DNA replication. Slx4 interacts physically not only with Slx1, but also with Rad1–Rad10 [XPF (xeroderma pigmentosum complementation group F)–ERCC1 (excision repair cross-complementing 1) in humans], another structure-specific endonuclease that participates in the repair of UV-induced DNA damage and in a subpathway of recombinational DNA DSB (double-strand break) repair. Curiously, Slx4 is essential for repair of DSBs by Rad1–Rad10, but is not required for repair of UV damage. Slx4 also promotes cellular resistance to DNA-alkylating agents that block the progression of replisomes during DNA replication, by facilitating the error-free mode of lesion bypass. This does not require Slx1 or Rad1–Rad10, and so Slx4 has several distinct roles in protecting genome stability. In the present article, I provide an overview of our current understanding of the cellular roles of the Slx proteins, paying particular attention to the advances that have been made in understanding the cellular roles of Slx4. In particular, protein–protein interactions and underlying molecular mechanisms are discussed and I draw attention to the many questions that have yet to be answered.

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Identification of S-phase DNA damage-response targets in fission yeast reveals conservation of damage-response networks

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1525620113 ◽

2016 ◽

Vol 113 (26) ◽

pp. E3676-E3685 ◽

Cited By ~ 8

Author(s):

Nicholas A. Willis ◽

Chunshui Zhou ◽

Andrew E. H. Elia ◽

Johanne M. Murray ◽

Antony M. Carr ◽

...

Keyword(s):

Gene Expression ◽

Dna Damage ◽

Dna Replication ◽

Fission Yeast ◽

Dna Damage Response ◽

Cellular Response ◽

Genome Stability ◽

Biological Significance ◽

S Phase ◽

Damage Response

The cellular response to DNA damage during S-phase regulates a complicated network of processes, including cell-cycle progression, gene expression, DNA replication kinetics, and DNA repair. In fission yeast, this S-phase DNA damage response (DDR) is coordinated by two protein kinases: Rad3, the ortholog of mammalian ATR, and Cds1, the ortholog of mammalian Chk2. Although several critical downstream targets of Rad3 and Cds1 have been identified, most of their presumed targets are unknown, including the targets responsible for regulating replication kinetics and coordinating replication and repair. To characterize targets of the S-phase DDR, we identified proteins phosphorylated in response to methyl methanesulfonate (MMS)-induced S-phase DNA damage in wild-type, rad3∆, and cds1∆ cells by proteome-wide mass spectrometry. We found a broad range of S-phase–specific DDR targets involved in gene expression, stress response, regulation of mitosis and cytokinesis, and DNA replication and repair. These targets are highly enriched for proteins required for viability in response to MMS, indicating their biological significance. Furthermore, the regulation of these proteins is similar in fission and budding yeast, across 300 My of evolution, demonstrating a deep conservation of S-phase DDR targets and suggesting that these targets may be critical for maintaining genome stability in response to S-phase DNA damage across eukaryotes.

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Sensing R-Loop-Associated DNA Damage to Safeguard Genome Stability

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.618157 ◽

2021 ◽

Vol 8 ◽

Author(s):

Carlo Rinaldi ◽

Paolo Pizzul ◽

Maria Pia Longhese ◽

Diego Bonetti

Keyword(s):

Dna Damage ◽

Cellular Response ◽

Genome Stability ◽

Genome Instability ◽

Hybrid Structure ◽

Physiological Processes ◽

Dna Strand ◽

Template Dna ◽

Dna Substrate

DNA transcription and replication are two essential physiological processes that can turn into a threat for genome integrity when they compete for the same DNA substrate. During transcription, the nascent RNA strongly binds the template DNA strand, leading to the formation of a peculiar RNA–DNA hybrid structure that displaces the non-template single-stranded DNA. This three-stranded nucleic acid transition is called R-loop. Although a programed formation of R-loops plays important physiological functions, these structures can turn into sources of DNA damage and genome instability when their homeostasis is altered. Indeed, both R-loop level and distribution in the genome are tightly controlled, and the list of factors involved in these regulatory mechanisms is continuously growing. Over the last years, our knowledge of R-loop homeostasis regulation (formation, stabilization, and resolution) has definitely increased. However, how R-loops affect genome stability and how the cellular response to their unscheduled formation is orchestrated are still not fully understood. In this review, we will report and discuss recent findings about these questions and we will focus on the role of ATM- and Rad3-related (ATR) and Ataxia–telangiectasia-mutated (ATM) kinases in the activation of an R-loop-dependent DNA damage response.

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Transcriptional Regulation of thep53Tumor Suppressor Gene in S-Phase of the Cell-Cycle and the Cellular Response to DNA Damage

Biochemistry Research International ◽

10.1155/2012/808934 ◽

2012 ◽

Vol 2012 ◽

pp. 1-5 ◽

Cited By ~ 24

Author(s):

David Reisman ◽

Paula Takahashi ◽

Amanda Polson ◽

Kristy Boggs

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Transcriptional Regulation ◽

Cellular Response ◽

Genome Stability ◽

Suppressor Gene ◽

S Phase ◽

Dna Binding Factors ◽

Combined Action ◽

Cellular Stressors

Thep53tumor suppressor induces the transcription of genes that negatively regulate progression of the cell cycle in response to DNA damage or other cellular stressors and thus participates in maintaining genome stability. Numerous studies have demonstrated thatp53transcription is activated before or during early S-phase in cells progressing from G0/G1into S-phase through the combined action of two DNA-binding factors RBP-Jκand C/EBPβ-2. Here, we review evidence that this induction occurs to provide availablep53mRNA in order to prepare the cell for DNA damage in S-phase, this ensuring a rapid response to DNA damage before exiting this stage of the cell cycle.

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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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N6-Methyladenosine, DNA Repair, and Genome Stability

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.645823 ◽

2021 ◽

Vol 8 ◽

Author(s):

Fei Qu ◽

Pawlos S. Tsegay ◽

Yuan Liu

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Cellular Response ◽

Genome Stability ◽

Fine Tuning ◽

Genome Integrity ◽

Cell Renewal ◽

The Novel ◽

Cellular Sensitivity

N6-methyladenosine (m6A) modification in mRNAs and non-coding RNAs is a newly identified epitranscriptomic mark. It provides a fine-tuning of gene expression to serve as a cellular response to endogenous and exogenous stimuli. m6A is involved in regulating genes in multiple cellular pathways and functions, including circadian rhythm, cell renewal, differentiation, neurogenesis, immunity, among others. Disruption of m6A regulation is associated with cancer, obesity, and immune diseases. Recent studies have shown that m6A can be induced by oxidative stress and DNA damage to regulate DNA repair. Also, deficiency of the m6A eraser, fat mass obesity-associated protein (FTO) can increase cellular sensitivity to genotoxicants. These findings shed light on the novel roles of m6A in modulating DNA repair and genome integrity and stability through responding to DNA damage. In this mini-review, we discuss recent progress in the understanding of a unique role of m6As in mRNAs, lncRNAs, and microRNAs in DNA damage response and regulation of DNA repair and genome integrity and instability.

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Bifidobacterium infantis Maintains Genome Stability in Ulcerative Colitis via Regulating Anaphase-Promoting Complex Subunit 7

Frontiers in Microbiology ◽

10.3389/fmicb.2021.761113 ◽

2021 ◽

Vol 12 ◽

Author(s):

Taotao Han ◽

Xiaomin Hu ◽

Kemin Li ◽

Di Zhang ◽

Yan Zhang ◽

...

Keyword(s):

Ulcerative Colitis ◽

Dna Damage ◽

Genome Stability ◽

Cell Model ◽

Host Genome ◽

Bacterial Invasion ◽

Signal Pathways ◽

Anaphase Promoting Complex ◽

Bifidobacterium Infantis ◽

Colitis Model

Probiotics represents a promising intestinal microbiota-targeted therapeutic method for the treatment of ulcerative colitis (UC). Several lines of evidence implicate that Bifidobacterium infantis serves as a probiotic strain with proven efficacy in maintaining the remission of UC. However, the exact mechanisms underlying the beneficial effects of B. infantis on UC progression have yet to be elucidated. Herein, we provide evidence that B. infantis acts as a key predisposing factor for the maintenance of host genome stability. First, we showed that the fecal microbiota transplantation (FMT) of UC-derived feces contributes to more severely DNA damage in dextran sodium sulfate (DSS)-induced mice likely due to mucosa-associated microbiota alterations, as reflected by the rapid appearance of DNA double strand breaks (DSBs), a typical marker of genome instability. Genomic DNA damage analysis of colon tissues derived from healthy controls, patients with UC or dysplasia, and colitis associated cancer (CAC) patients, revealed an enhanced level of DSBs with aggravation in the degree of the intestinal mucosal lesions. To evaluate whether B. infantis modulates the host genome stability, we employed the DSS-induced colitis model and a TNFα-induced intestinal epithelial cell model. Following the administration of C57BL/6 mice with B. infantis via oral gavage, we found that the development of DSS-induced colitis in mice was significantly alleviated, in contrast to the colitis model group. Notably, B. infantis administration decreased DSB levels in both DSS-induced colitis and TNF-treated colonial cell model. Accordingly, our bioinformatic and functional studies demonstrated that B. infantis altered signal pathways involved in ubiquitin-mediated proteolysis, transcriptional misregulation in cancer, and the bacterial invasion of epithelial cells. Mechanistically, B. infantis upregulated anaphase-promoting complex subunit 7 (APC7), which was significantly suppressed in colitis condition, to activate the DNA repair pathway and alter the genome stability, while downregulation of APC7 abolished the efficiency of B. infantis treatment to induce a decrease in the level of DSBs in TNFα-induced colonial cells. Collectively, our results support that B. infantis orchestrates a molecular network involving in APC7 and genome stability, to control UC development at the clinical, biological, and mechanistic levels. Supplying B. infantis and targeting its associated pathway will yield valuable insight into the clinical management of UC patients.

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Human papillomavirus 16 E6 expression disrupts the p53-mediated cellular response to DNA damage.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.90.9.3988 ◽

1993 ◽

Vol 90 (9) ◽

pp. 3988-3992 ◽

Cited By ~ 307

Author(s):

T. D. Kessis ◽

R. J. Slebos ◽

W. G. Nelson ◽

M. B. Kastan ◽

B. S. Plunkett ◽

...

Keyword(s):

Dna Damage ◽

Human Papillomavirus ◽

Cellular Response ◽

Human Papillomavirus 16

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The Integration Pattern of Human Papillomavirus in the Host Genome as a Promising Guide for Precise Radiation Therapy in Cervical Cancer

Precision Medicine and Clinical OMICS ◽

10.5812/pmco.115501 ◽

2021 ◽

Vol 1 (1) ◽

Author(s):

Mansoureh Gorginzadeh ◽

Mahsa Motavaf

Keyword(s):

Cervical Cancer ◽

Human Papillomavirus ◽

Case Reports ◽

Locally Advanced ◽

Case Series ◽

Concurrent Chemotherapy ◽

Human Papillomaviruses ◽

Host Genome ◽

Hpv Dna ◽

Integration Pattern

Context: Cervical cancer (CC) is one of the most common cancers among women worldwide. Infection with high-risk human papillomavirus (HPV) is the leading risk factor for this cancer. Currently, concurrent chemotherapy and radiotherapy are the standard of care for patients with locally advanced CC. However, the response to radiotherapy varies widely among patients, underscoring the need to identify biomarkers to predict patients’ treatment outcomes. Evidence Acquisition: In order to find relevant articles, we performed a systematic search using ISI Web of Science, Scopus, PubMed, and Embase, with a combination of the keywords “human papillomaviruses”, “cervical cancer”, “radiotherapy”, “biomarkers”, “viral integration”, and “episome”. All types of studies, including observational or retrospective studies, clinical trials, congress abstracts, and case reports or case series, were examined to find relevant data. No time limitation was considered for the studies. Results: The integration of HPV DNA into the host genome is considered to be a critical step in HPV carcinogenesis. The HPV integration pattern has been investigated as a potent prognostic factor for the tailored treatment of CC. Conclusions: It is indicated that the integration state of the HPV genome in host DNA is a potential prognostic or predictive biomarker for CC response to radiotherapy.

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