2022
DOI: 10.1158/0008-5472.can-21-2101
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p16 Represses DNA Damage Repair via a Novel Ubiquitin-Dependent Signaling Cascade

Abstract: Squamous cell carcinoma driven by human papillomavirus (HPV) is more sensitive to DNAdamaging therapies than its HPV-negative counterpart. Here we show that p16, the clinically utilized surrogate for HPV positivity, renders cells more sensitive to radiation via a ubiquitindependent signaling pathway, linking high levels of this protein to increased activity of the transcription factor SP1, increased HUWE1 transcription, and degradation of ubiquitin-specific protease 7 (USP7) and TRIP12. Activation of this path… Show more

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Cited by 19 publications
(14 citation statements)
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References 55 publications
(71 reference statements)
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“…This was mechanistically explained by a decreased expression of the Rad51 loading factors BRCA2 or Cyclin D1, with the latter being a consequence of the high p16 levels in these cells (8)(9)(10). p16 was further reported to cause a decrease in TRIP12 expression and subsequently an increase in the ubiquitin ligase RNF168, which was also described to result in defective DSB repair, presumably by interfering with HR (11,12). Intriguingly, the E7 oncoprotein from high-risk HPV-types was recently shown to bind RNF168 and impede its function at DSBs, leading to enhanced repair by HR (13).…”
Section: Introductionmentioning
confidence: 99%
“…This was mechanistically explained by a decreased expression of the Rad51 loading factors BRCA2 or Cyclin D1, with the latter being a consequence of the high p16 levels in these cells (8)(9)(10). p16 was further reported to cause a decrease in TRIP12 expression and subsequently an increase in the ubiquitin ligase RNF168, which was also described to result in defective DSB repair, presumably by interfering with HR (11,12). Intriguingly, the E7 oncoprotein from high-risk HPV-types was recently shown to bind RNF168 and impede its function at DSBs, leading to enhanced repair by HR (13).…”
Section: Introductionmentioning
confidence: 99%
“…Furthermore, inhibitors of electron transport chain complexes, TCA cycle enzymes, and glutamine metabolism in clinical trials for various treatment-refractory cancers (47) may have value for a subset of HPV+ OPSCCs of similar metabolic phenotype. Although aggressively targeting oxidative metabolism in the clinic remains hampered by toxicity, the severely impaired DNA damage repair phenotype in HPV+ OPSCCs (3) may widen the therapeutic window by allowing responses at lower drug doses than those needed for other cancers.…”
Section: Discussionmentioning
confidence: 99%
“…The seven treatment-naïve HPV+ OPSCC PDXs used in this study were established and passaged as described by us in the subcutaneous flank of NSG mice (22). The PDXs were harvested for RNAseq in triplicate upon reaching 1cm 3 . Volumes were calculated as width 2 x length/2.…”
Section: Growth and Rna Sequencing Of Pdxsmentioning
confidence: 99%
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“…The MTT assay was performed similar to previous publication with the following modifications (43). Depending on cell line, 1,000-4,000 cells per well in 100 μL of media were plated into 96-well plates.…”
Section: Methodsmentioning
confidence: 99%