DNA damage signalling barrier, oxidative stress and treatment-relevant DNA repair factor alterations during progression of human prostate cancer.
Molecular Oncology 10(6):879 (2016)
The DNA damage checkpoints provide an anti-cancer barrier in diverse tumour types, however this concept has remained unexplored in prostate cancer (CaP). Furthermore, targeting DNA repair defects by PARP1 inhibitors (PARPi) as a cancer treatment strategy is emerging yet requires suitable predict...
TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity.
Journal of Cell Biology 212(3):281 (2016)
Topoisomerase IIβ-binding protein 1 (TOPBP1) participates in DNA replication and DNA damage response; however, its role in DNA repair and relevance for human cancer remain unclear. Here, through an unbiased small interfering RNA screen, we identified and validated TOPBP1 as a novel determinant w...
A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer
Cell 162(5):1169 (2015)
A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer.
Cell 162(1):146 (2015)
KRAS is one of the most frequently mutated oncogenes in human cancer. Despite substantial efforts, no clinically applicable strategy has yet been developed to effectively treat KRAS-mutant tumors. Here, we perform a cell-line-based screen and identify strong synergistic interactions between cell...
REV7 counteracts DNA double-strand break resection and affects PARP inhibition.
Nature 521(7553):541 (2015)
Error-free repair of DNA double-strand breaks (DSBs) is achieved by homologous recombination (HR), and BRCA1 is an important factor for this repair pathway. In the absence of BRCA1-mediated HR, the administration of PARP inhibitors induces synthetic lethality of tumour cells of patients with bre...
Myc and Ras oncogenes engage different energy metabolism programs and evoke distinct patterns of oxidative and DNA replication stress.
Molecular Oncology 9(3):601 (2015)
Both Myc and Ras oncogenes impact cellular metabolism, deregulate redox homeostasis and trigger DNA replication stress (RS) that compromises genomic integrity. However, how are such oncogene-induced effects evoked and temporally related, to what extent are these kinetic parameters shared by Myc ...
TRIP12 and UBR5 Suppress Spreading of Chromatin Ubiquitylation at Damaged Chromosomes
Cell 159(6):1476 (2014)
Patterns of DNA damage response in intracranial germ cell tumors versus glioblastomas reflect cell of origin rather than brain environment: implications for the anti-tumor barrier concept and treatment.
Molecular Oncology 8(8):1667 (2014)
The DNA damage response (DDR) machinery becomes commonly activated in response to oncogenes and during early stages of development of solid malignancies, with an exception of testicular germ cell tumors (TGCTs). The active DDR signaling evokes cell death or senescence but this anti-tumor barrier...
A short acidic motif in ARF guards against mitochondrial dysfunction and melanoma susceptibility.
Nature Communications 5:5348 (2014)
ARF is a small, highly basic protein that can be induced by oncogenic stimuli and exerts growth-inhibitory and tumour-suppressive activities through the activation of p53. Here we show that, in human melanocytes, ARF is cytoplasmic, constitutively expressed, and required for maintaining low stea...
JMJD1C demethylates MDC1 to regulate the RNF8 and BRCA1-mediated chromatin response to DNA breaks.
Nature Structural & Molecular Biology 20(12):1425 (2013)
Chromatin ubiquitylation flanking DNA double-strand breaks (DSBs), mediated by RNF8 and RNF168 ubiquitin ligases, orchestrates a two-branch pathway, recruiting repair factors 53BP1 or the RAP80-BRCA1 complex. We report that human demethylase JMJD1C regulates the RAP80-BRCA1 branch of this DNA-da...
Androgen receptor signaling fuels DNA repair and radioresistance in prostate cancer.
Cancer Discovery 3(11):1222 (2013)
Successful treatment by genotoxic modalities including radiotherapy is commonly hampered by treatment resistance in advanced cancers. Two new studies now reveal that androgen receptor signaling transcriptionally upregulates a large subset of DNA repair genes, thereby enhancing the repair capacit...
Functional interplay between the DNA-damage-response kinase ATM and ARF tumour suppressor protein in human cancer.
Nature Cell Biology 15(8):967 (2013)
The DNA damage response (DDR) pathway and ARF function as barriers to cancer development. Although commonly regarded as operating independently of each other, some studies proposed that ARF is positively regulated by the DDR. Contrary to either scenario, we found that in human oncogene-transform...
Evaluation of candidate biomarkers to predict cancer cell sensitivity or resistance to PARP-1 inhibitor treatment.
Cell Cycle 11(20):3837 (2012)
Impaired DNA damage response pathways may create vulnerabilities of cancer cells that can be exploited therapeutically. One such selective vulnerability is the sensitivity of BRCA1- or BRCA2-defective tumors (hence defective in DNA repair by homologous recombination, HR) to inhibitors of the pol...
Utilization of fluorescence in situ hybridization with cytokeratin discriminators in TOP2A assessment of chemotherapy-treated patients with breast cancer.
Human Pathology 43(9):1363 (2012)
Tumor biomarkers increasingly provide information for predicting outcomes with chemotherapeutic regimens (personalized medicine). Topo2A is a DNA helicase targeted by anthracyclines, cytotoxic therapeutics used in both adjuvant and palliative treatments of breast cancer. TOP2A gene amplification...
TRIP12 and UBR5 suppress spreading of chromatin ubiquitylation at damaged chromosomes.
Cell 150(4):697 (2012)
Histone ubiquitylation is a prominent response to DNA double-strand breaks (DSBs), but how these modifications are confined to DNA lesions is not understood. Here, we show that TRIP12 and UBR5, two HECT domain ubiquitin E3 ligases, control accumulation of RNF168, a rate-limiting component of a p...
DNA damage response and inflammatory signaling limit the MLL-ENL-induced leukemogenesis in vivo.
Cancer Cell 21(4):517 (2012)
Activation of the MLL-ENL-ERtm oncogene initiates aberrant proliferation of myeloid progenitors. Here, we show induction of a fail-safe mechanism mediated by the DNA damage response (DDR) machinery that results in activation of the ATR/ATM-Chk1/Chk2-p53/p21(CIP1) checkpoint and cellular senescen...
NQO1 expression correlates inversely with NFκB activation in human breast cancer.
Breast Cancer Research and Treatment 132(3):955 (2012)
NQO1 participates in cellular defense against oxidative stress and regulates apoptosis via p53- and NFκB-mediated pathways. We have previously found that homozygous missense variant NQO1*2 (rs1800566) predicts poor survival among breast cancer patients, particularly after anthracycline-based adj...
Autocrine VEGF-VEGFR2-Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth.
Journal of Experimental Medicine 209(3):507 (2012)
Although vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) is traditionally regarded as an endothelial cell protein, evidence suggests that VEGFRs may be expressed by cancer cells. Glioblastoma multiforme (GBM) is a lethal cancer characterized by florid vascularization and aberrantly...
Thresholds of replication stress signaling in cancer development and treatment.
Nature Structural & Molecular Biology 19(1):5 (2012)
Macrophages, nitric oxide and microRNAs are associated with DNA damage response pathway and senescence in inflammatory bowel disease.
PLoS ONE 7(9):e44156 (2012)
Cellular senescence can be a functional barrier to carcinogenesis. We hypothesized that inflammation modulates carcinogenesis through senescence and DNA damage response (DDR). We examined the association between senescence and DDR with macrophage levels in inflammatory bowel disease (IBD). In vi...