Retinoblastoma family proteins: New players in DNA repair by non-homologous end-joining

Huang, Paul H.; Cook, Rebecca S.; Zoumpoulidou, Georgia; Luczynski, Maciej T.; Mittnacht, Sibylle

doi:10.1080/23723556.2015.1053596

Cited by 7 publications

(6 citation statements)

References 24 publications

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“…RB1 is a tumor suppressor protein, which inhibits cell cycle progression from G1 to S phase. Recently, there is evidence supporting a direct functional involvement of RB1 protein in DNA repair by NHEJ [ 8 ]. Therefore, loss of function of ATM or RB1 protein may contribute to reduced DSB repair response and uncontrolled cell proliferation, which can lead to increased cancer susceptibility and vulnerability to radiotherapy or cytotoxic agents, e.g.…”

Section: Discussionmentioning

confidence: 99%

ATM/RB1 mutations predict shorter overall survival in urothelial cancer

et al. 2018

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BackgroundMutations of DNA repair genes, e.g. ATM/RB1, are frequently found in urothelial cancer (UC) and have been associated with better response to cisplatin-based chemotherapy. Further external validation of the prognostic value of ATM/RB1 mutations in UC can inform clinical decision making and trial designs.ResultsIn the discovery dataset, ATM/RB1 mutations were present in 24% of patients and were associated with shorter OS (adjusted HR 2.67, 95% CI, 1.45–4.92, p = 0.002). There was a higher mutation load in patients carrying ATM/RB1 mutations (median mutation load: 6.7 versus 5.5 per Mb, p = 0.072). In the validation dataset, ATM/RB1 mutations were present in 22.2% of patients and were non-significantly associated with shorter OS (adjusted HR 1.87, 95% CI, 0.97–3.59, p = 0.06) and higher mutation load (median mutation load: 8.1 versus 7.2 per Mb, p = 0.126).Materials and MethodsExome sequencing data of 130 bladder UC patients from The Cancer Genome Atlas (TCGA) dataset were analyzed as a discovery cohort to determine the prognostic value of ATM/RB1 mutations. Results were validated in an independent cohort of 81 advanced UC patients. Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI) to compare overall survival (OS).ConclusionsATM/RB1 mutations may be a biomarker of poor prognosis in unselected UC patients and may correlate with higher mutational load. Further studies are required to determine factors that can further stratify prognosis and evaluate predictive role of ATM/RB1 mutation status to immunotherapy and platinum-based chemotherapy.

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Section: Discussionmentioning

confidence: 99%

ATM/RB1 mutations predict shorter overall survival in urothelial cancer

et al. 2018

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“…This notion suggests that atypical E2Fs could potentially compensate for the loss of RB. In addition, both RB and atypical E2Fs are thought to play important roles in mediating DNA repair and cell cycle arrest in response to genotoxic reagents [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. Hence, to fully understand how control of E2F-dependent transcription affects tumorigenesis, their genetic interaction must be studied in vivo.…”

Section: Introductionmentioning

confidence: 99%

Atypical E2Fs either Counteract or Cooperate with RB during Tumorigenesis Depending on Tissue Context

Moreno

Pandit

Toussaint

et al. 2021

Cancers

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E2F-transcription factors activate many genes involved in cell cycle progression, DNA repair, and apoptosis. Hence, E2F-dependent transcription must be tightly regulated to prevent tumorigenesis, and therefore metazoan cells possess multiple E2F regulation mechanisms. The best-known is the Retinoblastoma protein (RB), which is mutated in many cancers. Atypical E2Fs (E2F7 and −8) can repress E2F-target gene expression independently of RB and are rarely mutated in cancer. Therefore, they may act as emergency brakes in RB-mutated cells to suppress tumor growth. Currently, it is unknown if and how RB and atypical E2Fs functionally interact in vivo. Here, we demonstrate that mice with liver-specific combinatorial deletion of Rb and E2f7/8 have reduced life-spans compared to E2f7/8 or Rb deletion alone. This was associated with increased proliferation and enhanced malignant progression of liver tumors. Hence, atypical repressor E2Fs and RB cooperatively act as tumor suppressors in hepatocytes. In contrast, loss of either E2f7 or E2f8 largely prevented the formation of pituitary tumors in Rb+/− mice. To test whether atypical E2Fs can also function as oncogenes independent of RB loss, we induced long-term overexpression of E2f7 or E2f8 in mice. E2F7 and −8 overexpression increased the incidence of tumors in the lungs, but not in other tissues. Collectively, these data show that atypical E2Fs can promote but also inhibit tumorigenesis depending on tissue type and RB status. We propose that the complex interactions between atypical E2Fs and RB on maintenance of genetic stability underlie this context-dependency.

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“…171 RB1, one of the p53-MDM2 interacting partner, regulates DNA damage repair by interacting with NHEJ proteins in the N-terminal domain. 172 By concurrently interacting with a number of proteins, such as histone deacetylases (HDACs) via the central pocket domain and the DNA damage repair protein TP53BP1 via methylated K810 in the C-terminal domain, RB1 promotes the recruitment of chromatin regulatory proteins to sites of DNA damage, thereby fostering the chromatin environment necessary for NHEJ. 173 The majority of p53-MDM2 modulators are engaged in NHEJ repair following HRR (Figure 3E).…”

Section: Negative Regulation Of Mdm2mentioning

confidence: 99%

Working title: Molecular involvement of p53‐MDM2 interactome in gastrointestinal cancers

Yedla,

Bhamidipati,

Syed

et al. 2024

Cell Biochemistry & Function

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The interaction between murine double minute 2 (MDM2) and p53, marked by transcriptional induction and feedback inhibition, orchestrates a functional loop dictating cellular fate. The functional loop comprising p53‐MDM2 axis is made up of an interactome consisting of approximately 81 proteins, which are spatio‐temporally regulated and involved in DNA repair mechanisms. Biochemical and genetic alterations of the interactome result in dysregulation of the p53‐mdm2 axis that leads to gastrointestinal (GI) cancers. A large subset of interactome is well known and it consists of proteins that either stabilize p53 or MDM2 and proteins that target the p53‐MDM2 complex for ubiquitin‐mediated destruction. Upstream signaling events brought about by growth factors and chemical messengers invoke a wide variety of posttranslational modifications in p53‐MDM2 axis. Biochemical changes in the transactivation domain of p53 impact the energy landscape, induce conformational switching, alter interaction potential and could change solubility of p53 to redefine its co‐localization, translocation and activity. A diverse set of chemical compounds mimic physiological effectors and simulate biochemical modifications of the p53‐MDM2 interactome. p53‐MDM2 interactome plays a crucial role in DNA damage and repair process. Genetic aberrations in the interactome, have resulted in cancers of GI tract (pancreas, liver, colorectal, gastric, biliary, and esophageal). We present in this article a review of the overall changes in the p53‐MDM2 interactors and the effectors that form an epicenter for the development of next‐generation molecules for understanding and targeting GI cancers.

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Retinoblastoma family proteins: New players in DNA repair by non-homologous end-joining

Cited by 7 publications

References 24 publications

ATM/RB1 mutations predict shorter overall survival in urothelial cancer

ATM/RB1 mutations predict shorter overall survival in urothelial cancer

Atypical E2Fs either Counteract or Cooperate with RB during Tumorigenesis Depending on Tissue Context

Working title: Molecular involvement of p53‐MDM2 interactome in gastrointestinal cancers

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