HPV and DNA repair
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ABSTRACT:
PROVIDER: PRJEB54747 | ENA |
REPOSITORIES: ENA
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Project description:A growing proportion of head and neck squamous cell carcinomas (HNSCC) is associated with the human papilloma virus (HPV), particularly HPV16. We compare tumors with different HPV16 DNA and RNA (E6*I) status from 290 consecutively recruited HNSCC patients by gene expression profiling and targeted sequencing of 50 genes. We confirm that the HPV16 DNA+ RNA+ tumors are molecularly distinct from the HPV-negative (DNA-) HNSCC and have elevated expression of cell cycle genes and rare TP53 mutations (3.6%, 1/28). We show that tumors with non-transcriptionally active HPV16 (DNA+ RNA-) are similar to HPV DNA- tumors regarding gene expression and frequency of TP53 mutations (47%, 8/17 and 43%, 72/167, respectively). Furthermore, we identify four gene expression clusters. They moderately but significantly differ in overall survival. One cluster exhibits high expression of immune response genes (IR) and contains most of the HPV16 DNA+ RNA+ patients. The IR cluster and disruptive TP53 mutations are associated with lymph node metastasis independent of HPV16 status and we validate each of these associations in another large data set. Consistent with earlier studies, disruptive TP53 mutations are prognostically unfavorable. Our findings underscore the importance of measuring the HPV16 RNA (E6*I) and TP53-mutation status for patient stratification and for the first time identify associations of an immune response-related gene expression cluster and TP53 mutations with lymph node metastasis in HNSCC.
2015-06-24 | GSE65858 | GEO
Project description:Aim was to identify cellular factors that regulate HPV-16 late gene expression at the level of RNA processing Cervical cancer cells permissive for HPV16 late gene expression were identified and characterized. These cells either contained a novel spliced variant of the L1 mRNAs that bypassed the suppressed HPV16 late, 5’-splice site SD3632, produced elevated levels of RNA-binding proteins SRSF1 (ASF/SF2), SRSF9 (SRp30c) and HuR that are known to regulate HPV16 late gene expression, or were shown by a gene expression array analysis to overexpress the RALYL RNA-binding protein of the hnRNP C-family. Overexpression of RALYL, or RALY and hnRNP C1 that are two other members of the hnRNP C-family, induced HPV16 late gene expression from HPV16 subgenomic plasmids and from episomal forms of the full-length HPV16 genome. Induction of HPV16 late gene expression by the hnRNP C-proteins was dependent on the HPV16 early untranslated region to which these proteins also were shown to bind in vitro, and in living cells. Our experiments revealed that hnRNP C proteins that interacted with the HPV16 early untranslated region reached out to the splicing silencer complex at HPV16 SD3632 and derepressed this splice site, thereby activating production of HPV16 spliced late L1 mRNAs. In conclusion, hnRNP C- proteins bind to the HPV16 early untranslated region and control of HPV16 late L1 mRNA splicing.
2015-06-12 | GSE65166 | GEO
Project description:HPV integrated site capture (HISC) protocol used to detect HPV16 integration breakpoints in the genomes of W12 cell lines. Biotinylated HPV16-specific RNA baits were used to capture HPV16-human breakpoint junctions in genomic DNA.
2021-06-18 | E-MTAB-10154 | biostudies-arrayexpress
Project description:The human papillomavirus (HPV) genome is integrated into host DNA in most HPV-positive cancers, but the consequences for chromosomal integrity are unknown. Continuous long-read sequencing of oropharyngeal cancers and cancer cell lines revealed a unique form of structural variation, termed heterocateny here, characterized by heterogeneous, interrelated, and repetative patterns of concatemerized virus and host DNA segments. Evidence of heterocateny was detected in extrachromosomal and/or intrachromosomal DNA in all cases. Unique breakpoint sequences shared across structurally heterogeneous virus-host concatemers within each cancer facilitated stepwise reconstruction of their evolution from a common molecular ancestor. This analysis revealed that unstable virus and virus-host concatemers in ecDNA or integrated form mediate insertion into and excision from chromosomes, capture, rearrangement, and rolling-circle amplification of host DNA, and chromosomal rearrangements. The data indicate that heterocatena is driven by the dynamic, aberrant replication and recombination of an oncogenic DNA virus, thereby extending known consequences of HPV integration to include promotion of intra-tumoral heterogeneity and clonal evolution.
| EGAS00001006652 | EGA
Project description:HPV E6 from the genus alpha 'high risk' types such as HPV16 recruit the ubiquitin ligase E6AP to ubiquitinate p53 and target it for proteasome-mediated degradation. This results in the functional inactivation of p53 in HPV16-E6 expressing cells. To test what patterns in gene expression might change as a result of HPV16 E6 protein functions and to test whether HPV E6 proteins from genus beta virus types also inactivate p53, we profiled gene expression using Affymetrix arrays before and after stimulating p53 activity via DNA damage in a panel of N/Tert-E6 cell lines.
2013-09-05 | GSE50568 | GEO
Project description:Formation of a repair enzyme complex is beneficial to DNA repair. Despite cellular studies showed that mitochondrial DNA polymerase (Pol ) and poly(ADP-ribose) polymerase 1 (PARP1) were found in the same complex along with other mitochondrial DNA repair enzymes and mitochondrial PARP1 level is correlated with mtDNA integrity, the molecular basis for the functional connection between Pol and PARP1 has not been illustrated, because cellular functions of PARP1 in DNA repair are intertwined with metabolism via NAD+ (nicotinamide adenosine dinucleotide), the substrate of PARP1 and a metabolic cofactor. To dissect the direct effect of PARP1 on mtDNA from the secondary perturbation metabolism, we report here biochemical studies that recapitulated Pol PARylation observed in cells, showed that PARP1 regulates Pol activity during DNA repair in a metabolic cofactor NAD+ (nicotinamide adenosine dinucleotide)-dependent manner. In the absence of NAD+, PARP1 completely inhibits Pol, while increasing NAD+ level to physiological concentration enables Pol to resume maximum repair activity. Because cellular NAD+ levels are linked to metabolism and to ATP production via oxidative phosphorylation, our results suggest that mtDNA damage repair is correlated with cellular metabolic state and integrity of the respiratory chain.
2020-12-16 | MSV000086606 | MassIVE
Project description:It is well known that high-risk human papilloma virus (HR-HPV) infection is strongly associated with cervical cancer and E7 was identified as one of the key initiators in HPV-mediated carcinogenesis. Here we show that lactate dehydrogenase A (LDHA) preferably locates in the nucleus in HPV16-positive cervical tumors due to E7-induced intracellular reactive oxygen species (ROS) accumulation. Surprisingly, nuclear LDHA gains a non-canonical enzyme activity to produce α-hydroxybutyrate and triggers DOT1L (disruptor of telomeric silencing 1-like)-mediated histone H3K79 hypermethylation, resulting in the activation of antioxidant responses and Wnt signaling pathway. Furthermore, HPV16 E7 knocking-out reduces LDHA nuclear translocation and H3K79 tri-methylation in K14-HPV16 transgenic mouse model. HPV16 E7 level is significantly positively correlated with nuclear LDHA and H3K79 tri-methylation in cervical cancer. Collectively, our findings uncover a non-canonical enzyme activity of nuclear LDHA to epigenetically control cellular redox balance and cell proliferation facilitating HPV-induced cervical cancer development.
2018-09-24 | PXD011058 | Pride
Project description:A growing proportion of head and neck squamous cell carcinomas (HNSCC) is associated with the human papilloma virus (HPV), particularly HPV16. We compare tumors with different HPV16 DNA and RNA (E6*I) status from 290 consecutively recruited HNSCC patients by gene expression profiling and targeted sequencing of 50 genes. We confirm that the HPV16 DNA+ RNA+ tumors are molecularly distinct from the HPV-negative (DNA-) HNSCC and have elevated expression of cell cycle genes and rare TP53 mutations (3.6%, 1/28). We show that tumors with non-transcriptionally active HPV16 (DNA+ RNA-) are similar to HPV DNA- tumors regarding gene expression and frequency of TP53 mutations (47%, 8/17 and 43%, 72/167, respectively). Furthermore, we identify four gene expression clusters. They moderately but significantly differ in overall survival. One cluster exhibits high expression of immune response genes (IR) and contains most of the HPV16 DNA+ RNA+ patients. The IR cluster and disruptive TP53 mutations are associated with lymph node metastasis independent of HPV16 status and we validate each of these associations in another large data set. Consistent with earlier studies, disruptive TP53 mutations are prognostically unfavorable. Our findings underscore the importance of measuring the HPV16 RNA (E6*I) and TP53-mutation status for patient stratification and for the first time identify associations of an immune response-related gene expression cluster and TP53 mutations with lymph node metastasis in HNSCC. A total of 300 samples were considered. Quality control procedures were applied to microarray probe-level intensity files. A total of 270 tumor arrays remained after removing low-quality arrays, duplicate arrays, and arrays from non-HNSCC samples. Expression values were log2-transformed and normalized using RSN.
2015-06-24 | E-GEOD-65858 | biostudies-arrayexpress
Project description:Aim was to identify cellular factors that regulate HPV-16 late gene expression at the level of RNA processing Cervical cancer cells permissive for HPV16 late gene expression were identified and characterized. These cells either contained a novel spliced variant of the L1 mRNAs that bypassed the suppressed HPV16 late, 5’-splice site SD3632, produced elevated levels of RNA-binding proteins SRSF1 (ASF/SF2), SRSF9 (SRp30c) and HuR that are known to regulate HPV16 late gene expression, or were shown by a gene expression array analysis to overexpress the RALYL RNA-binding protein of the hnRNP C-family. Overexpression of RALYL, or RALY and hnRNP C1 that are two other members of the hnRNP C-family, induced HPV16 late gene expression from HPV16 subgenomic plasmids and from episomal forms of the full-length HPV16 genome. Induction of HPV16 late gene expression by the hnRNP C-proteins was dependent on the HPV16 early untranslated region to which these proteins also were shown to bind in vitro, and in living cells. Our experiments revealed that hnRNP C proteins that interacted with the HPV16 early untranslated region reached out to the splicing silencer complex at HPV16 SD3632 and derepressed this splice site, thereby activating production of HPV16 spliced late L1 mRNAs. In conclusion, hnRNP C- proteins bind to the HPV16 early untranslated region and control of HPV16 late L1 mRNA splicing. Total cellular RNA was extracted from stable cell lines. Samples were prepared in triplicates. C33ARSVNeo served as control cell line.
2015-06-12 | E-GEOD-65166 | biostudies-arrayexpress
Project description:Human papillomavirus (HPV) induced immortalization of human foreskin keratinocytes (HFK) is a two-step process, including 1) the bypass of replicative senescence and acquisition of an extended lifespan, and 2) the outgrowth of immortal cells. Our previous study showed that the immortalization capacity of HPV is type dependent, as reflected by the presence or absence of a crisis period before reaching immortality. In the present study we determined how the HPV-type specific immortalization capacity relates to DNA damage induction and overall genomic instability. Early passage HFKs transduced with HPV types 16, 18, 31, 33, 35, 45, 51, 59, 66 and 70 showed an increased number of double strand DNA breaks compared to controls, without significant differences between the various HPV-types. However, immortal descendants of HPV-transduced HFKs that underwent a crisis period (HPV45-, 51-, 59-, 66- and 70-transduced HFKs) showed significantly more chromosomal aberrations compared to those without a crisis period (HPV16-, 18-, 31-, and 35-transduced HFKs) (p<0.01). In particular, regions on chromosome 5p, 8, and 9q were significantly more frequently altered in cells with crisis. Interestingly, the hTERT locus at 5p was exclusively gained in cell lines with crisis. Chromothripsis was detected in one of the HPV16-immortalized cell lines in which multiple rearrangements within chromosome 8 resulted in a gain of c-MYC. In conclusion, the present study shows that upon HPV-induced immortalization, the number of chromosomal aberrations is inversely related to the immortalization capacity of the virus type. This suggests that hrHPV types with reduced immortalization capacity in vitro, as reflected by a crisis period, require more genetic host cell aberrations to trigger immortalization.
2016-08-01 | GSE72063 | GEO