Androgen Receptor Signaling Regulates DNA Repair in Prostate Cancers

“We demonstrate that the androgen receptor (AR) regulates a transcriptional program of DNA repair genes that promotes prostate cancer radioresistance, providing a potential mechanism by which androgen deprivation therapy (ADT) synergizes with ionizing radiation (IR). Using a model of castration-resistant prostate cancer, we show that second-generation antiandrogen therapy results in downregulation of DNA repair genes. Next, we demonstrate that primary prostate cancers display a significant spectrum of AR transcriptional output which correlates with expression of a set of DNA repair genes. Employing RNA-seq and ChIP-seq, we define which of these DNA repair genes are both induced by androgen and represent direct AR targets. We establish that prostate cancer cells treated with IR plus androgen demonstrate enhanced DNA repair and decreased DNA damage and furthermore that antiandrogen treatment causes increased DNA damage and decreased clonogenic survival. Finally, we demonstrate that antiandrogen treatment results in decreased classical non-homologous end joining.”


TMPRSS2-ERG Status Is Not Prognostic Following Prostate Cancer Radiotherapy: Implications for Fusion Status and DSB Repair

“BACKGROUND: Pre-clinical data suggest that TMPRSS2-ERG gene fusions, present in about 50% of prostate cancers (PCa), may be a surrogate for DNA repair status and therefore a biomarker for DNA damaging agents. To test this hypothesis, we examined whether TMPRSS2-ERG status was associated with biochemical failure after clinical induction of DNA damage following image-guided radiotherapy (IGRT). METHODS: Pre-treatment biopsies from two cohorts of intermediate-risk PCa patients (T1/T2, GS < 8, PSA < 20ng/mL) (> 7 years follow-up) were analyzed: (1) 126 patients with DNA samples assayed by array Comparative Genomic Hybridization for TMPRSS2-ERG fusion (CGH-cohort); and (2), 118 patients whose biopsies were scored within a tissue microarray (TMA) immunostained for ERG overexpression (surrogate for TMPRSS2-ERG fusion) (IHC-cohort). Patients were treated with IGRT with a median dose of 76 Gy. The potential role of TMPRSS2-ERG status as a prognostic factor for biochemical relapse-free rate (bRFR; nadir + 2 ng/mL) was evaluated in the context of clinical prognostic factors in multivariate analyses using Cox proportional hazards models. RESULTS: TMPRSS2-ERG fusion by aCGH was identified in 27 patients (21%) in the CGH-cohort and ERG overexpression was found in 59 patients (50%) in the IHC-cohort. In both cohorts TMPRSS2-ERG status was not associated with bRFR on univariate or multivariate analyses. CONCLUSIONS: In two similarly-treated IGRT cohorts, TMPRSS2-ERG status was not prognostic for bRFR, in disagreement with the hypothesis that these PCa have DNA repair defects that render them clinically more radiosensitive. TMPRSS2-ERG is therefore unlikely to be a predictive factor for IGRT response.”


Catastrophic Nuclear Envelope Collapse in Cancer Cell Micronuclei

“During mitotic exit, missegregated chromosomes can recruit their own nuclear envelope (NE) to form micronuclei (MN). MN have reduced functioning compared to primary nuclei in the same cell, although the two compartments appear to be structurally comparable. Here we show that over 60% of MN undergo an irreversible loss of compartmentalization during interphase due to NE collapse. This disruption of the MN, which is induced by defects in nuclear lamina assembly, drastically reduces nuclear functions and can trigger massive DNA damage. MN disruption is associated with chromatin compaction and invasion of endoplasmic reticulum (ER) tubules into the chromatin. We identified disrupted MN in both major subtypes of human non-small-cell lung cancer, suggesting that disrupted MN could be a useful objective biomarker for genomic instability in solid tumors. Our study shows that NE collapse is a key event underlying MN dysfunction and establishes a link between aberrant NE organization and aneuploidy.”


Catastrophic Nuclear Envelope Collapse in Cancer Cell Micronuclei

“During mitotic exit, missegregated chromosomes can recruit their own nuclear envelope (NE) to form micronuclei (MN). MN have reduced functioning compared to primary nuclei in the same cell, although the two compartments appear to be structurally comparable. Here we show that over 60% of MN undergo an irreversible loss of compartmentalization during interphase due to NE collapse. This disruption of the MN, which is induced by defects in nuclear lamina assembly, drastically reduces nuclear functions and can trigger massive DNA damage. MN disruption is associated with chromatin compaction and invasion of endoplasmic reticulum (ER) tubules into the chromatin. We identified disrupted MN in both major subtypes of human non-small-cell lung cancer, suggesting that disrupted MN could be a useful objective biomarker for genomic instability in solid tumors. Our study shows that NE collapse is a key event underlying MN dysfunction and establishes a link between aberrant NE organization and aneuploidy.”


Catastrophic Nuclear Envelope Collapse in Cancer Cell Micronuclei

“During mitotic exit, missegregated chromosomes can recruit their own nuclear envelope (NE) to form micronuclei (MN). MN have reduced functioning compared to primary nuclei in the same cell, although the two compartments appear to be structurally comparable. Here we show that over 60% of MN undergo an irreversible loss of compartmentalization during interphase due to NE collapse. This disruption of the MN, which is induced by defects in nuclear lamina assembly, drastically reduces nuclear functions and can trigger massive DNA damage. MN disruption is associated with chromatin compaction and invasion of endoplasmic reticulum (ER) tubules into the chromatin. We identified disrupted MN in both major subtypes of human non-small-cell lung cancer, suggesting that disrupted MN could be a useful objective biomarker for genomic instability in solid tumors. Our study shows that NE collapse is a key event underlying MN dysfunction and establishes a link between aberrant NE organization and aneuploidy.”


Aspirin May Fight Cancer by Slowing DNA Damage

“Aspirin is known to lower risk for some cancers, and a new study led by a UC San Francisco scientist points to a possible explanation, with the discovery that aspirin slows the accumulation of DNA mutations in abnormal cells in at least one pre-cancerous condition.”


Aspirin May Fight Cancer by Slowing DNA Damage

“Aspirin is known to lower risk for some cancers, and a new study led by a UC San Francisco scientist points to a possible explanation, with the discovery that aspirin slows the accumulation of DNA mutations in abnormal cells in at least one pre-cancerous condition.”


Aspirin May Fight Cancer by Slowing DNA Damage

“Aspirin is known to lower risk for some cancers, and a new study led by a UC San Francisco scientist points to a possible explanation, with the discovery that aspirin slows the accumulation of DNA mutations in abnormal cells in at least one pre-cancerous condition.”


Human ALKBH7 is Required for Alkylation and Oxidation-Induced Programmed Necrosis

“Programmed necrosis has emerged as a crucial modulator of cell death in response to several forms of cellular stress. In one form of programmed necrotic cell death, induced by cytotoxic alkylating agents, hyperactivation of poly-ADP-ribose polymerase (PARP) leads to cellular NAD and ATP depletion, mitochondrial dysfunction, reactive oxygen species formation, and ensuing cell death. Here, we show that the protein encoded by the human AlkB homolog 7 (ALKBH7) gene plays a pivotal role in DNA-damaging agent-induced programmed necrosis by triggering tha collapse of…”