Recombination Repair

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Thomas Helleday - One of the best experts on this subject based on the ideXlab platform.

  • Timeless Interacts with PARP-1 to Promote Homologous Recombination Repair
    Molecular cell, 2015
    Co-Authors: Si Xie, Thomas Helleday, Oliver Mortusewicz, Hoi Tang, Patrick Herr, Randy Yat Choi Poon, Chengmin Qian
    Abstract:

    Human Timeless helps stabilize replication forks during normal DNA replication and plays a critical role in activation of the S phase checkpoint and proper establishment of sister chromatid cohesion. However, it remains elusive whether Timeless is involved in the Repair of damaged DNA. Here, we identify that Timeless physically interacts with PARP-1 independent of poly(ADP-ribosyl)ation. We present high-resolution crystal structures of Timeless PAB (PARP-1-binding domain) in free form and in complex with PARP-1 catalytic domain. Interestingly, Timeless PAB domain specifically recognizes PARP-1, but not PARP-2 or PARP-3. Timeless-PARP-1 interaction does not interfere with PARP-1 enzymatic activity. We demonstrate that rapid and transient accumulation of Timeless at laser-induced DNA damage sites requires PARP-1, but not poly(ADP-ribosyl)ation and that Timeless is co-trapped with PARP-1 at DNA lesions upon PARP inhibition. Furthermore, we show that Timeless and PARP-1 interaction is required for efficient homologous Recombination Repair.

  • Ionizing radiation induces replication-associated secondary DNA double-strand breaks that are substrates for homologous Recombination Repair
    2011
    Co-Authors: Petra Groth, Ingegerd Elvers, Manuel Luis Orta, Muntasir Mamun Majumder, Anne Lagerqvist, Thomas Helleday
    Abstract:

    Ionizing radiation induces replication-associated secondary DNA double-strand breaks that are substrates for homologous Recombination Repair

  • Homologous Recombination Repair is essential for Repair of vosaroxin-induced DNA double-strand breaks
    Oncotarget, 2010
    Co-Authors: Rachael E. Hawtin, Cecilia Lundin, Thomas Helleday, David E. Stockett, Oi Kwan Wong, Judith A. Fox
    Abstract:

    Vosaroxin (formerly voreloxin) is a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II, inducing site-selective double-strand breaks (DSB), G2 arrest and apoptosis. Objective responses and complete remissions were observed in phase 2 studies of vosaroxin in patients with solid and hematologic malignancies, and responses were seen in patients whose cancers were resistant to anthracyclines. The quinolone-based scaffold differentiates vosaroxin from the anthracyclines and anthracenediones, broadly used DNA intercalating topoisomerase II poisons. Here we report that vosaroxin induces a cell cycle specific pattern of DNA damage and Repair that is distinct from the anthracycline, doxorubicin. Both drugs stall replication and preferentially induce DNA damage in replicating cells, with damage in G2 / M > S >> G1. However, detectable replication fork collapse, as evidenced by DNA fragmentation and long tract Recombination during S phase, is induced only by doxorubicin. Furthermore, vosaroxin induces less overall DNA fragmentation. Homologous Recombination Repair (HRR) is critical for recovery from DNA damage induced by both agents, identifying the potential to clinically exploit synthetic lethality.

  • Transcription inhibition by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) causes DNA damage and triggers homologous Recombination Repair in mammalian cells.
    Mutation Research, 2010
    Co-Authors: Ivaylo Stoimenov, Ponnari Gottipati, Niklas Schultz, Thomas Helleday
    Abstract:

    Transcription, replication and homologous Recombination are intrinsically connected and it is well established that an increase of transcription is associated with an increase in homologous Recombination. Here, we have studied how homologous Recombination is affected during transcription inhibition by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB), a compound that prevents activating phosphorylations of the RNA Pol II C-terminal domain. We identify that DRB triggers an increase in homologous Recombination within the hprt gene as well as increasing RAD51 foci formation in mammalian cells. Furthermore, we find that DRB-induced transcriptional stress is associated with formation of the nuclear foci of the phosphorylated form of H2AX (γH2AX). We accounted that about 72% of RAD51 foci co-localized with the observed γH2AX foci. Interestingly, we find that XRCC3 mutated, homologous Recombination defective cells are hypersensitive to the toxic effect of DRB and fail to form RAD51 foci. In conclusion, we show that DRB-induced transcription inhibition is associated with the formation of a lesion that triggers RAD51-dependent homologous Recombination Repair, required for survival under transcriptional stress.

  • Targeting homologous Recombination Repair defects in cancer.
    Trends in pharmacological sciences, 2010
    Co-Authors: Bastiaan Evers, Thomas Helleday, Jos Jonkers
    Abstract:

    DNA Repair is essential for cells to maintain genome stability in an environment that constantly produces DNA damage. There is a growing appreciation that defects in homologous Recombination Repair underlie hereditary and sporadic tumourigenesis, and that deficiency in this pathway may dictate the sensitivity of tumours to certain DNA-damaging agents. Homologous Recombination deficiency (HRD) may therefore prove to be a diagnostic criterion per se if appropriate biomarkers become available to identify these tumours. In addition, homologous Recombination-deficient tumours are more sensitive to inhibition of other DNA Repair pathways through so-called 'synthetic lethal interactions', a principle that is currently being tested in clinical trials. Finally, homologous Recombination Repair-deficient cells may have an increased dependency on certain cell-cycle checkpoints, which can be therapeutically exploited. Here we describe recent advances in strategies to identify and target HRD tumours, approaches to overcome resistance, and combinatory strategies to optimize treatment outcome.

Beata Smolarz - One of the best experts on this subject based on the ideXlab platform.

  • New single nucleotide polymorphisms (SNPs) in homologous Recombination Repair genes detected by microarray analysis in Polish breast cancer patients.
    Clinical and experimental medicine, 2016
    Co-Authors: Hanna Romanowicz, Dominik Strapagiel, Marcin Słomka, Marta Sobalska-kwapis, Ewa Kępka, Anna Siewierska-górska, Marek Zadrożny, Jan Bieńkiewicz, Beata Smolarz
    Abstract:

    Breast cancer is the most common cause of malignancy and mortality in women worldwide. This study aimed at localising homologous Recombination Repair (HR) genes and their chromosomal loci and correlating their nucleotide variants with susceptibility to breast cancer. In this study, authors analysed the association between single nucleotide polymorphisms (SNPs) in homologous Recombination Repair genes and the incidence of breast cancer in the population of Polish women. Blood samples from 94 breast cancer patients were analysed as test group. Individuals were recruited into the study at the Department of Oncological Surgery and Breast Diseases of the Institute of the Polish Mother's Memorial Hospital in Lodz, Poland. Healthy controls (n = 500) were obtained from the Biobank Laboratory, Department of Molecular Biophysics, University of Lodz. Then, DNA of breast cancer patients was compared with one of the disease-free women. The test was supported by microarray analysis. Statistically significant correlations were identified between breast cancer and 3 not described previously SNPs of homologous Recombination Repair genes BRCA1 and BRCA2: rs59004709, rs4986852 and rs1799950. Further studies on larger groups are warranted to support the hypothesis of correlation between the abovementioned genetic variants and breast cancer risk.

  • New single nucleotide polymorphisms (SNPs) in homologous Recombination Repair genes detected by microarray analysis in Polish breast cancer patients
    2016
    Co-Authors: Hanna Romanowicz, Dominik Strapagiel, Marcin Słomka, Marta Sobalska-kwapis, Ewa Kępka, Anna Siewierska-górska, Marek Zadrożny, Beata Smolarz
    Abstract:

    Purpose of the study: Breast cancer is the most common cause of malignancy mortality in women worldwide. This study aimed at localising homologous Recombination Repair (HR) genes and their chromosomal loci and correlating their nucleotide variants with susceptibility to breast cancer. In this study authors analysed the association between single nucleotide polymorphisms (SNPs) in homologous Recombination Repair genes and the incidence of breast cancer in the population of Polish women. Methods: Blood samples from 94 breast cancer patients were analysed as test group. Individuals were recruited into the study at the Department of Oncological Surgery and Breast Diseases of the Institute of the Polish Mother Memorial Hospital in Lodz, Poland. Healthy controls (n=500) were obtained from the Biobank Laboratory, Department of Molecular Biophysics, University of Lodz. Then, DNA of breast cancer patients was compared with one of disease-free women. The test was supported by microarray analysis. Results: Statistically significant correlations were identified between breast cancer and 3 not described previously single nucleotide polymorphisms (SNPs) of homologous Recombination Repair genes BRCA1 and BRCA2: rs59004709, rs4986852 and rs1799950. Conclusions: Further studies on larger groups are warranted to support the hypothesis of correlation between the above-mentioned genetic variants and breast cancer risk.

  • Single nucleotide polymorphisms in the homologous Recombination Repair genes and breast cancer risk in Polish women.
    The Tohoku journal of experimental medicine, 2011
    Co-Authors: Hanna Romanowicz-makowska, Marek Zadrożny, Beata Smolarz, Bogusław Westfal, Jakub Baszczyński, Ireneusz Połać, Stanisław Sporny
    Abstract:

    Genetic polymorphisms in homologous Recombination Repair genes that can lead to protein haploinsufficiency are generally associated with increased cancer risk. The aim of the present study was to evaluate associations between the risk of breast cancer and single nucleotide polymorphisms in the genes, encoding three key proteins of the homologous Recombination Repair: RAD51 (the human homologue of the E. coli RecA protein), X-ray Repair cross-complementing group (XRCC) 2 and XRCC3. The polymorphisms studied were G135C of the RAD51 gene (c. -98 G>C; rs1801320), Arg188His of the XRCC2 gene (c. 563 G>A; rs3218536), and Thr241Met of the XRCC3 gene (c. 722 C>T; rs861539). Each polymorphism was genotyped by the PCR-RFLP (restriction fragment-length polymorphism) method in 700 Polish female patients with sporadic breast cancer and in 708 cancer-free women, who served as controls. In the present study, we showed the association between RAD51 G135C polymorphism and the incidence of breast cancer (p < 0.0001), but found no significant association with XRCC2 Arg188His or XRCC3 Thr241Met polymorphism. Instead, significant association was identified between XRCC2 Arg188His or XRCC3 Thr241Met polymorphism and breast cancer progression, assessed by the histological grading. However, each of these three polymorphisms was not associated with the tumor size or the lymph node metastases. This study provides evidence that links single nucleotide polymorphisms of RAD51 and XRCC2/3 genes with the risk of breast cancer in Polish women. In conclusion, RAD51 G135C, XRCC2 Arg188His and XRCC3 Thr241Met polymorphisms may be regarded as predictive factors of sporadic breast cancer in female population.

Kristoffer Valerie - One of the best experts on this subject based on the ideXlab platform.

  • extracellular signal related kinase positively regulates ataxia telangiectasia mutated homologous Recombination Repair and the dna damage response
    Cancer Research, 2007
    Co-Authors: Sarah E. Golding, Steven J. Neill, Paul Dent, Lawrence F. Povirk, Elizabeth Rosenberg, Kristoffer Valerie
    Abstract:

    The accurate joining of DNA double-strand breaks by homologous Recombination Repair (HRR) is critical to the long-term survival of the cell. The three major mitogen-activated protein (MAP) kinase (MAPK) signaling pathways, extracellular signal-regulated kinase (ERK), p38, and c-Jun-NH2-kinase (JNK), regulate cell growth, survival, and apoptosis. To determine the role of MAPK signaling in HRR, we used a human in vivo I-SceI–based Repair system. First, we verified that this Repair platform is amenable to pharmacologic manipulation and show that the ataxia telangiectasia mutated (ATM) kinase is critical for HRR. The ATM-specific inhibitor KU-55933 compromised HRR up to 90% in growth-arrested cells, whereas this effect was less pronounced in cycling cells. Then, using well-characterized MAPK small-molecule inhibitors, we show that ERK1/2 and JNK signaling are important positive regulators of HRR in growth-arrested cells. On the other hand, inhibition of the p38 MAPK pathway generated an almost 2-fold stimulation of HRR. When ERK1/2 signaling was stimulated by oncogenic RAF-1, an ∼2-fold increase in HRR was observed. KU-55933 partly blocked radiation-induced ERK1/2 phosphorylation, suggesting that ATM regulates ERK1/2 signaling. Furthermore, inhibition of MAP/ERK kinase (MEK)/ERK signaling resulted in severely reduced levels of phosphorylated (S1981) ATM foci but not γ-H2AX foci, and suppressed ATM phosphorylation levels >85% throughout the cell cycle. Collectively, these results show that MAPK signaling positively and negatively regulates HRR in human cells. More specifically, ATM-dependent signaling through the RAF/MEK/ERK pathway is critical for efficient HRR and for radiation-induced ATM activation, suggestive of a regulatory feedback loop between ERK and ATM. [Cancer Res 2007;67(3):1046–53]

  • extracellular signal related kinase positively regulates ataxia telangiectasia mutated homologous Recombination Repair and the dna damage response
    Cancer Research, 2007
    Co-Authors: Sarah E. Golding, Steven J. Neill, Paul Dent, Lawrence F. Povirk, Elizabeth Rosenberg, Kristoffer Valerie
    Abstract:

    The accurate joining of DNA double-strand breaks by homologous Recombination Repair (HRR) is critical to the long-term survival of the cell. The three major mitogen-activated protein (MAP) kinase (MAPK) signaling pathways, extracellular signal-regulated kinase (ERK), p38, and c-Jun-NH(2)-kinase (JNK), regulate cell growth, survival, and apoptosis. To determine the role of MAPK signaling in HRR, we used a human in vivo I-SceI-based Repair system. First, we verified that this Repair platform is amenable to pharmacologic manipulation and show that the ataxia telangiectasia mutated (ATM) kinase is critical for HRR. The ATM-specific inhibitor KU-55933 compromised HRR up to 90% in growth-arrested cells, whereas this effect was less pronounced in cycling cells. Then, using well-characterized MAPK small-molecule inhibitors, we show that ERK1/2 and JNK signaling are important positive regulators of HRR in growth-arrested cells. On the other hand, inhibition of the p38 MAPK pathway generated an almost 2-fold stimulation of HRR. When ERK1/2 signaling was stimulated by oncogenic RAF-1, an approximately 2-fold increase in HRR was observed. KU-55933 partly blocked radiation-induced ERK1/2 phosphorylation, suggesting that ATM regulates ERK1/2 signaling. Furthermore, inhibition of MAP/ERK kinase (MEK)/ERK signaling resulted in severely reduced levels of phosphorylated (S1981) ATM foci but not gamma-H2AX foci, and suppressed ATM phosphorylation levels >85% throughout the cell cycle. Collectively, these results show that MAPK signaling positively and negatively regulates HRR in human cells. More specifically, ATM-dependent signaling through the RAF/MEK/ERK pathway is critical for efficient HRR and for radiation-induced ATM activation, suggestive of a regulatory feedback loop between ERK and ATM.

Sarah E. Golding - One of the best experts on this subject based on the ideXlab platform.

  • extracellular signal related kinase positively regulates ataxia telangiectasia mutated homologous Recombination Repair and the dna damage response
    Cancer Research, 2007
    Co-Authors: Sarah E. Golding, Steven J. Neill, Paul Dent, Lawrence F. Povirk, Elizabeth Rosenberg, Kristoffer Valerie
    Abstract:

    The accurate joining of DNA double-strand breaks by homologous Recombination Repair (HRR) is critical to the long-term survival of the cell. The three major mitogen-activated protein (MAP) kinase (MAPK) signaling pathways, extracellular signal-regulated kinase (ERK), p38, and c-Jun-NH(2)-kinase (JNK), regulate cell growth, survival, and apoptosis. To determine the role of MAPK signaling in HRR, we used a human in vivo I-SceI-based Repair system. First, we verified that this Repair platform is amenable to pharmacologic manipulation and show that the ataxia telangiectasia mutated (ATM) kinase is critical for HRR. The ATM-specific inhibitor KU-55933 compromised HRR up to 90% in growth-arrested cells, whereas this effect was less pronounced in cycling cells. Then, using well-characterized MAPK small-molecule inhibitors, we show that ERK1/2 and JNK signaling are important positive regulators of HRR in growth-arrested cells. On the other hand, inhibition of the p38 MAPK pathway generated an almost 2-fold stimulation of HRR. When ERK1/2 signaling was stimulated by oncogenic RAF-1, an approximately 2-fold increase in HRR was observed. KU-55933 partly blocked radiation-induced ERK1/2 phosphorylation, suggesting that ATM regulates ERK1/2 signaling. Furthermore, inhibition of MAP/ERK kinase (MEK)/ERK signaling resulted in severely reduced levels of phosphorylated (S1981) ATM foci but not gamma-H2AX foci, and suppressed ATM phosphorylation levels >85% throughout the cell cycle. Collectively, these results show that MAPK signaling positively and negatively regulates HRR in human cells. More specifically, ATM-dependent signaling through the RAF/MEK/ERK pathway is critical for efficient HRR and for radiation-induced ATM activation, suggestive of a regulatory feedback loop between ERK and ATM.

  • extracellular signal related kinase positively regulates ataxia telangiectasia mutated homologous Recombination Repair and the dna damage response
    Cancer Research, 2007
    Co-Authors: Sarah E. Golding, Steven J. Neill, Paul Dent, Lawrence F. Povirk, Elizabeth Rosenberg, Kristoffer Valerie
    Abstract:

    The accurate joining of DNA double-strand breaks by homologous Recombination Repair (HRR) is critical to the long-term survival of the cell. The three major mitogen-activated protein (MAP) kinase (MAPK) signaling pathways, extracellular signal-regulated kinase (ERK), p38, and c-Jun-NH2-kinase (JNK), regulate cell growth, survival, and apoptosis. To determine the role of MAPK signaling in HRR, we used a human in vivo I-SceI–based Repair system. First, we verified that this Repair platform is amenable to pharmacologic manipulation and show that the ataxia telangiectasia mutated (ATM) kinase is critical for HRR. The ATM-specific inhibitor KU-55933 compromised HRR up to 90% in growth-arrested cells, whereas this effect was less pronounced in cycling cells. Then, using well-characterized MAPK small-molecule inhibitors, we show that ERK1/2 and JNK signaling are important positive regulators of HRR in growth-arrested cells. On the other hand, inhibition of the p38 MAPK pathway generated an almost 2-fold stimulation of HRR. When ERK1/2 signaling was stimulated by oncogenic RAF-1, an ∼2-fold increase in HRR was observed. KU-55933 partly blocked radiation-induced ERK1/2 phosphorylation, suggesting that ATM regulates ERK1/2 signaling. Furthermore, inhibition of MAP/ERK kinase (MEK)/ERK signaling resulted in severely reduced levels of phosphorylated (S1981) ATM foci but not γ-H2AX foci, and suppressed ATM phosphorylation levels >85% throughout the cell cycle. Collectively, these results show that MAPK signaling positively and negatively regulates HRR in human cells. More specifically, ATM-dependent signaling through the RAF/MEK/ERK pathway is critical for efficient HRR and for radiation-induced ATM activation, suggestive of a regulatory feedback loop between ERK and ATM. [Cancer Res 2007;67(3):1046–53]

  • MAPK signaling pathways positively and negatively regulate homologous Recombination Repair
    Cancer Research, 2006
    Co-Authors: Sarah E. Golding, Steven J. Neill, Paul Dent, Lawrence F. Povirk, Kristoffer C. Valerie
    Abstract:

    Proc Amer Assoc Cancer Res, Volume 47, 2006 4385 DNA double-strand breaks (DSBs) occur in the cell either naturally through the stalling of replication forks, or artificially by an array of agents such as ionizing radiation and radiomimetic drugs. Despite their source, the accurate joining of DSBs by homologous Recombination Repair (HRR) is critical to the long term survival of the cell. The accumulation of breaks can lead to cell death by apoptosis, and inaccurate Repair increases genomic instability, mutations and malignancy. MAPK family signaling regulates growth, survival and apoptosis. The MAPKs have also been shown to be central to the cellular response to ionizing radiation. The three major MAPK signaling pathways ERK, p38 and JNK have been shown to have both collaborative and antagonistic effects on these major cellular processes. To determine how MAPK signaling affects HRR, an I-SceI based Repair assay was utilized in growth-arrested human glioma cells. The use of well-characterized inhibitors showed that ERK1/2 and JNK phosphorylation are important to HRR, blocking over 70% of HRR in both cases. In sharp contrast, inhibition of p38 MAPK stimulated HRR 1.4–1.7 fold. Interestingly, an increase in ERK1/2 phosphorylation was observed by western blotting when p38 MAPK was inhibited, suggesting the involvement of compensatory mechanisms. Further investigation of ERK1/2 involvement showed that when ERK1/2 signaling was stimulated by epidermal growth factor (EGF) a 2-fold increase in HRR was seen, which could be blocked by MEK1/2 inhibitors. These data suggest that EGF - MAPK signaling is involved in the regulation of HRR in human cells. It is clear that signaling through ERK1/2 and JNK is critical for efficient HRR and p38 MAPK signaling may exert a negative influence on ERK1/2 signaling and thus HRR. Supported by NIH CA72955.

Hanna Romanowicz - One of the best experts on this subject based on the ideXlab platform.

  • New single nucleotide polymorphisms (SNPs) in homologous Recombination Repair genes detected by microarray analysis in Polish breast cancer patients.
    Clinical and experimental medicine, 2016
    Co-Authors: Hanna Romanowicz, Dominik Strapagiel, Marcin Słomka, Marta Sobalska-kwapis, Ewa Kępka, Anna Siewierska-górska, Marek Zadrożny, Jan Bieńkiewicz, Beata Smolarz
    Abstract:

    Breast cancer is the most common cause of malignancy and mortality in women worldwide. This study aimed at localising homologous Recombination Repair (HR) genes and their chromosomal loci and correlating their nucleotide variants with susceptibility to breast cancer. In this study, authors analysed the association between single nucleotide polymorphisms (SNPs) in homologous Recombination Repair genes and the incidence of breast cancer in the population of Polish women. Blood samples from 94 breast cancer patients were analysed as test group. Individuals were recruited into the study at the Department of Oncological Surgery and Breast Diseases of the Institute of the Polish Mother's Memorial Hospital in Lodz, Poland. Healthy controls (n = 500) were obtained from the Biobank Laboratory, Department of Molecular Biophysics, University of Lodz. Then, DNA of breast cancer patients was compared with one of the disease-free women. The test was supported by microarray analysis. Statistically significant correlations were identified between breast cancer and 3 not described previously SNPs of homologous Recombination Repair genes BRCA1 and BRCA2: rs59004709, rs4986852 and rs1799950. Further studies on larger groups are warranted to support the hypothesis of correlation between the abovementioned genetic variants and breast cancer risk.

  • New single nucleotide polymorphisms (SNPs) in homologous Recombination Repair genes detected by microarray analysis in Polish breast cancer patients
    2016
    Co-Authors: Hanna Romanowicz, Dominik Strapagiel, Marcin Słomka, Marta Sobalska-kwapis, Ewa Kępka, Anna Siewierska-górska, Marek Zadrożny, Beata Smolarz
    Abstract:

    Purpose of the study: Breast cancer is the most common cause of malignancy mortality in women worldwide. This study aimed at localising homologous Recombination Repair (HR) genes and their chromosomal loci and correlating their nucleotide variants with susceptibility to breast cancer. In this study authors analysed the association between single nucleotide polymorphisms (SNPs) in homologous Recombination Repair genes and the incidence of breast cancer in the population of Polish women. Methods: Blood samples from 94 breast cancer patients were analysed as test group. Individuals were recruited into the study at the Department of Oncological Surgery and Breast Diseases of the Institute of the Polish Mother Memorial Hospital in Lodz, Poland. Healthy controls (n=500) were obtained from the Biobank Laboratory, Department of Molecular Biophysics, University of Lodz. Then, DNA of breast cancer patients was compared with one of disease-free women. The test was supported by microarray analysis. Results: Statistically significant correlations were identified between breast cancer and 3 not described previously single nucleotide polymorphisms (SNPs) of homologous Recombination Repair genes BRCA1 and BRCA2: rs59004709, rs4986852 and rs1799950. Conclusions: Further studies on larger groups are warranted to support the hypothesis of correlation between the above-mentioned genetic variants and breast cancer risk.