The Drivers, Mechanisms, and Consequences of Genome Instability in HPV-Driven Cancers

Cancers, Journal Year: 2022, Volume and Issue: 14(19), P. 4623 - 4623

Published: Sept. 23, 2022

Human papillomavirus (HPV) is the causative driver of cervical cancer and a contributing risk factor head neck several anogenital cancers. HPV’s ability to induce genome instability contributes its oncogenicity. HPV genes can in ways, including modulating cell cycle favour proliferation, interacting with DNA damage repair pathways bring high-fidelity viral episomes away from host genome, inducing DNA-damaging oxidative stress, altering length telomeres. In addition, presence chronic infection lead immune responses that also cause infected tissue. The become integrated into during HPV-induced tumorigenesis. Viral integration requires double-stranded breaks on DNA; therefore, regions around event are prone structural alterations themselves targets instability. this review, we present mechanisms by which HPV-dependent -independent initiated maintained HPV-driven cancers, both across at integration.

Language: Английский

---

A human papillomavirus 16 E2-TopBP1 dependent SIRT1-p300 acetylation switch regulates mitotic viral and human protein levels and activates the DNA damage response

mBio, Journal Year: 2024, Volume and Issue: 15(6)

Published: May 9, 2024

ABSTRACT An interaction between human papillomavirus 16 (HPV16) E2 and the cellular proteins TopBP1 BRD4 is required for plasmid segregation function. The E2-TopBP1 promotes increased mitotic protein levels in U2OS N/Tert-1 cells, as well foreskin keratinocytes immortalized by HPV16 (HFK + HPV16). SIRT1 deacetylation reduces stability here we demonstrate that acetylation occurs during mitosis a interacting-dependent manner, promoting stabilization. p300 mediates due to switching off function confirmed p53 on lysine 382, known target deacetylation. can complex with growing cells but unable do so interaction; also wild-type outside of mitosis. lysines 111 112 are highly conserved residues across all K111 hyper-acetylation mitosis, Topoisomerase 1 (Top1). We K112 ubiquitination proteasomal degradation CHK2, phosphorylation activation DNA damage response (DDR). results present new model which inactivates activates DDR. This novel mechanism DDR, requirement viral life cycle. IMPORTANCE Human papillomaviruses (HPVs) causative agents around 5% cancers. While there prophylactic vaccines will significantly alleviate HPV disease burden future generations, currently no anti-viral strategies available treatment To generate such reagents, must understand more about cycle, particular viral-host interactions. Here, describe generated interacting host controls deacetylase SIRT1. disrupts order enhance proteins. essential cycle represents therapeutic target.

Language: Английский

---

A Critical Role for p53 during the HPV16 Life Cycle

Microbiology Spectrum, Journal Year: 2022, Volume and Issue: 10(3)

Published: May 24, 2022

Human papillomaviruses (HPV) are causative agents in ano-genital and oral cancers; HPV16 is the most prevalent type detected human cancers. The E6 protein targets p53 for proteasomal degradation to facilitate proliferation of infected cell. However, immortalized cells predominantly spliced (E6*) unable degrade p53. Here, we demonstrate that foreskin keratinocytes by (HFK+HPV16), positive oropharyngeal cancers, retain significant expression In addition, levels increase HPV16+ head neck cancer cell lines following treatment with cisplatin. Introduction full-length into HFK+HPV16 resulted attenuation cellular growth (in hTERT HFK, promoted enhanced proliferation). An understudied interaction between E2 investigated whether this was important viral life cycle. We generated mutant genomes interact resulting profound phenotypes primary HFK. induced hyper-proliferation, but an ultimate arrest growth; β-galactosidase staining demonstrated increased senescence, COMET assays showed DNA damage compared wild-type cells. There failure cycle organotypic rafts HFK premature differentiation reduced proliferation. results critical during cycle, may be due a functional Disruption has antiviral potential.

Language: Английский

---

For Better or Worse: Modulation of the Host DNA Damage Response by Human Papillomavirus

Annual Review of Virology, Journal Year: 2023, Volume and Issue: 10(1), P. 325 - 345

Published: April 11, 2023

High-risk human papillomaviruses (HPVs) are associated with several cancers. HPVs small, DNA viruses that rely on host cell machinery for viral replication. The HPV life cycle takes place in the stratified epithelium, which is composed of different states, including terminally differentiating cells no longer active cycle. have evolved mechanisms to persist and replicate epithelium by hijacking modulating cellular pathways, damage response (DDR). activate exploit DDR pathways promote replication, turn increases susceptibility genomic instability carcinogenesis. Here, we review recent advances our understanding regulation high-risk during discuss potential consequences pathways.

Language: Английский

---

CK2 Phosphorylation of Human Papillomavirus 16 E2 on Serine 23 Promotes Interaction with TopBP1 and Is Critical for E2 Interaction with Mitotic Chromatin and the Viral Life Cycle

mBio, Journal Year: 2021, Volume and Issue: 12(5)

Published: Sept. 21, 2021

During the human papillomavirus 16 (HPV16) life cycle, E2 protein interacts with host factors to regulate viral transcription, replication, and genome segregation/retention. Our understanding of partner proteins their roles in functions remains incomplete. Here we demonstrate that CK2 phosphorylation on serine 23 promotes interaction TopBP1

Language: Английский

---

Research Status of Clustered Regulary Interspaced Short Palindromic Repeats Technology in the Treatment of Human Papillomavirus (HPV) Infection Related Diseases

Cancer Control, Journal Year: 2025, Volume and Issue: 32

Published: Jan. 1, 2025

Background: CRISPR/Cas9 technology has rapidly advanced as a pivotal tool in cancer research, particularly the precision targeting required for both detecting and treating malignancies. Its high specificity low off-target effects make it exceptionally effective applications involving Human Papillomavirus (HPV) related diseases, most notably cervical cancer. This approach offers refined methodology rapid detection of viral infections provides robust platform safe treatment diseases associated with through gene therapy. Purpose: Gene therapy, within this context, involves strategic delivery genetic material into target cells via vector. is followed by meticulous modulation expression, whether correction, addition, or suppression, specifically honed to tumor while sparing healthy cells. dual capacity diagnose treat at such precise level underscores transformative potential contemporary medical science, oncology virology. Research Design: article an overview advancements made utilizing CRISPR-Cas9 system research HPV-related treatments summarizing its application status basic diagnosis, HPV. Data Collection: Furthermore, discusses future prospects emerging areas HPV medicine clinical practice, highlighting technical challenges directions development.

Language: Английский

---

A human papillomavirus 16 E2-TopBP1 dependent SIRT1-p300 acetylation switch regulates mitotic viral and human protein levels

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 16, 2024

Abstract An interaction between human papillomavirus 16 (HPV16) E2 and the cellular proteins TopBP1 BRD4 is required for plasmid segregation function. The E2-TopBP1 promotes increased mitotic protein levels in U2OS N/Tert-1 cells, as well foreskin keratinocytes immortalized by HPV16 (HFK+HPV16). SIRT1 deacetylation reduces stability here we demonstrate that acetylation occurs during mitosis a interacting dependent manner, promoting stabilization. p300 mediates due to switching off function confirmed p53 on lysine 382, known target deacetylation. can complex with growing cells but unable do so interaction; also wild type outside of mitosis. lysines 111 112 are highly conserved residues across all K111 hyper-acetylation mitosis, Topoisomerase 1 (Top1). We K112 ubiquitination proteasomal degradation results present model which inactivates increases, Top1 protects from therefore degradation. Importance Human papillomaviruses causative agents around 5% cancers. While there prophylactic vaccines will significantly alleviate HPV disease burden future generations, currently no anti-viral strategies available treatment To generate such reagents, must understand more about life cycle, particular viral-host interactions. Here describe novel generated host controls deacetylase SIRT1. disrupts order enhance viral proteins. This essential cycle represents therapeutic target.

Language: Английский

---

RecQ Helicase Somatic Alterations in Cancer

Frontiers in Molecular Biosciences, Journal Year: 2022, Volume and Issue: 9

Published: June 15, 2022

Named the “caretakers” of genome, RecQ helicases function in several pathways to maintain genomic stability and repair DNA. This highly conserved family enzymes consist five different proteins humans: RECQL1, BLM, WRN, RECQL4, RECQL5. Biallelic germline mutations BLM , WRN RECQL4 have been linked rare cancer-predisposing syndromes. Emerging research has also implicated somatic alterations a variety cancers, including hematological malignancies, breast cancer, osteosarcoma, amongst others. These helicases, particularly overexpression, may lead increased resistance cancer cells conventional chemotherapy. Downregulation these allow for sensitivity chemotherapy, and, therefore, be important therapeutic targets. Here we provide comprehensive review our current understanding role DNA discuss potential opportunities targeting helicases.

Language: Английский

---

Like Brothers in Arms: How Hormonal Stimuli and Changes in the Metabolism Signaling Cooperate, Leading HPV Infection to Drive the Onset of Cervical Cancer

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(9), P. 5050 - 5050

Published: May 2, 2022

Despite all precautionary actions and the possibility of using vaccinations to counteract infections caused by human papillomaviruses (HPVs), HPV-related cancers still account for approximately 5% carcinomas. Worldwide, many women are excluded from adequate health care due their social position origin. Therefore, immense efforts in research therapy required challenges that this disease entails. The special thing about an HPV infection is it not only able trick immune system a sophisticated way, but also, through genetic integration into host genome, use resources available cells complete replication cycle virus without activating alarm mechanisms recognition elimination. utilized metabolic, immune, hormonal signaling pathways manipulates. Since dependent on enzymes cells, also intervenes cell differentiating keratinocytes shifts terminal differentiation uppermost layers squamocolumnar transformation zone (TZ) cervix. individual closely related equally important successful onset cervical cancer. We will therefore analyze effects metabolic signaling, as well changes tumor its microenvironment understand how each level interacts promote tumorigenesis

Language: Английский

---

Description of CRISPR-Cas9 development and its prospects in human papillomavirus-driven cancer treatment

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Nov. 21, 2022

Human papillomaviruses (HPVs) have been recognized as the etiologic agents of various cancers and are called HPV-driven cancers. Concerning HPV-mediated carcinogenic action, gene therapy can cure cancer at molecular level by means correction specific genes or sites. CRISPR-Cas9, a novel genetic editing technique, correct errors in genome change expression function cells efficiently, quickly, with relative ease. Herein, we overviewed studies CRISPR-mediated remedies for summarized potential applications CRISPR-Cas9 cancer.

Language: Английский

---