scholarly journals Differential Contributions of Mammalian Rad54 Paralogs to Recombination, DNA Damage Repair, and Meiosis

2006 ◽  
Vol 26 (3) ◽  
pp. 976-989 ◽  
Author(s):  
Joanna Wesoly ◽  
Sheba Agarwal ◽  
Stefan Sigurdsson ◽  
Wendy Bussen ◽  
Stephen Van Komen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Mitomycin C ◽  
Es Cells ◽  
Dna Damage Repair ◽  
Embryonic Stem ◽  
Biochemical Properties ◽  
Meiotic Chromosomes ◽  
Recombination Efficiency ◽  
Damage Repair

ABSTRACT Homologous recombination is a versatile DNA damage repair pathway requiring Rad51 and Rad54. Here we show that a mammalian Rad54 paralog, Rad54B, displays physical and functional interactions with Rad51 and DNA that are similar to those of Rad54. While ablation of Rad54 in mouse embryonic stem (ES) cells leads to a mild reduction in homologous recombination efficiency, the absence of Rad54B has little effect. However, the absence of both Rad54 and Rad54B dramatically reduces homologous recombination efficiency. Furthermore, we show that Rad54B protects ES cells from ionizing radiation and the interstrand DNA cross-linking agent mitomycin C. Interestingly, at the ES cell level the paralogs do not display an additive or synergic interaction with respect to mitomycin C sensitivity, yet animals lacking both Rad54 and Rad54B are dramatically sensitized to mitomycin C compared to either single mutant. This suggests that the paralogs possibly function in a tissue-specific manner. Finally, we show that Rad54, but not Rad54B, is needed for a normal distribution of Rad51 on meiotic chromosomes. Thus, even though the paralogs have similar biochemical properties, genetic analysis in mice uncovered their nonoverlapping roles.

scholarly journals Differentiation of Human Induced Pluripotent or Embryonic Stem Cells Decreases the DNA Damage Repair by Homologous Recombination

2017 ◽  
Vol 9 (5) ◽  
pp. 1660-1674 ◽  
Author(s):  
Kalpana Mujoo ◽  
Raj K. Pandita ◽  
Anjana Tiwari ◽  
Vijay Charaka ◽  
Sharmistha Chakraborty ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Embryonic Stem Cells ◽  
Homologous Recombination ◽  
Dna Damage Repair ◽  
Embryonic Stem ◽  
Damage Repair ◽  
Induced Pluripotent

The Rad17 homologue ofArabidopsisis involved in the regulation of DNA damage repair and homologous recombination

2004 ◽  
Vol 38 (6) ◽  
pp. 954-968 ◽  
Author(s):  
Fabian Heitzeberg ◽  
I-Peng Chen ◽  
Frank Hartung ◽  
Nadiya Orel ◽  
Karel J. Angelis ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Dna Damage Repair ◽  
Damage Repair

scholarly journals Wilms’ tumor gene WT1 promotes homologous recombination‐mediated DNA damage repair

2014 ◽  
Vol 54 (12) ◽  
pp. 1758-1771 ◽  
Author(s):  
Yusuke Oji ◽  
Naoya Tatsumi ◽  
Junya Kobayashi ◽  
Mari Fukuda ◽  
Tazu Ueda ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Wilms Tumor ◽  
Dna Damage Repair ◽  
Wilms Tumor Gene ◽  
Damage Repair ◽  
Tumor Gene

scholarly journals Molecular and Clinical Significance of Stanniocalcin-1 Expression in Breast Cancer Through Promotion of Homologous Recombination-Mediated DNA Damage Repair

2021 ◽  
Vol 9 ◽  
Author(s):  
Jing Hou ◽  
Jigan Cheng ◽  
ZeHua Dai ◽  
Na Wei ◽  
Huan Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Dna Damage Repair ◽  
Breast Cancer Cell Lines ◽  
Enzyme Linked Immunosorbent Assay ◽  
Glycoprotein Hormone ◽  
Damage Repair

Stanniocalcin-1 (STC1) is a glycoprotein hormone whose abnormal expression has been reported to be associated with a variety of tumors, but its function in breast cancer is not well understood. Through modulation of STC1 expression in different breast cancer cell lines, our study found that STC1 could promote the proliferation and growth of breast cancer cells and promote metastasis. Furthermore, STC1 reduced apoptosis induction by irradiation. We also found that STC1 could promote a homologous recombination-mediated DNA damage repair by recruiting BRCA1 to sites of damage. Moreover, STC1 silencing sensitized breast cancer cells to treatment with irradiation (IR), olaparib, or cisplatin in vitro. In clinical settings, the serum concentration of STC1 was higher in breast cancer patients than in healthy women, as detected by enzyme-linked immunosorbent assay (ELISA). In addition, immunohistochemical staining of breast cancer specimens showed that a high expression of STC1 was negatively correlated with recurrence-free survival in breast cancer, indicating that STC1 expression could be used as a predictive marker for a poor prognosis in breast cancer. All these findings indicate that STC1 promotes breast cancer tumorigenesis and that breast cancers with a high level of STC1 are more resistant to treatment, probably through homologous recombination (HR) promotion. Furthermore, combining STC1 inhibition and DNA damage-inducing drugs may be a novel approach to improve the survival of patients with STC1-expressing breast cancer.

scholarly journals The tumor suppressor BRCA1/BARD1 complex localizes to the synaptonemal complex and regulates recombination under meiotic dysfunction in Caenorhabditis elegans

2018 ◽  
Author(s):  
Qianyan Li ◽  
Takamune T. Saito ◽  
Alison J. Deshong ◽  
Marina Martinez Garcia ◽  
Saravanapriah Nadarajan ◽  
...  
Keyword(s):  
Dna Damage ◽  
Caenorhabditis Elegans ◽  
Tumor Suppressor ◽  
Homologous Recombination ◽  
Synaptonemal Complex ◽  
Meiotic Recombination ◽  
Dna Damage Repair ◽  
Chromosome Synapsis ◽  
Brca1 Mutations ◽  
Damage Repair

AbstractBreast cancer susceptibility gene 1(BRCA1) and binding partner BRCA1-associated RING domain protein 1 (BARD1) form an essential E3 ubiquitin ligase important for DNA damage repair and homologous recombination. In Caenorhabditis elegans BRCA1/BRC-1 and BARD1/BRD-1 orthologs are not essential, but function in DNA damage repair and homologous recombination, as well as in meiosis. In proliferating germ cells and in early meiotic prophase, BRC-1 and BRD-1 are nucleoplasmic, with enrichment at foci that partially overlap with the recombinase RAD-51. In mid-pachytene, BRC-1 and BRD-1 are observed on tracks, before concentrating to the short arms of bivalents, co-localizing with a central region component of the synaptonemal complex. We found that BRD-1 is essential for BRC-1 to associate with chromatin and the synaptonemal complex, but BRC-1 is not required for BRD-1 localization; the complex fails to properly localize in the absence of either meiotic recombination or chromosome synapsis. Inactivation of BRC-1/BRD-1 enhances the embryonic lethality of mutants that perturb chromosome synapsis and crossover recombination, suggesting that BRC-1/BRD-1 plays an important role in monitoring recombination in the context of the synaptonemal complex. We discovered that BRC-1/BRD-1 stabilizes the RAD51 filament when the formation of a crossover-intermediate is disrupted. Further, in the absence of BRC-1/BRD-1 crossover distribution is altered, and under meiotic dysfunction, crossover numbers are perturbed. Together, our studies indicate that BRC-1/BRD-1 localizes to the synaptonemal complex where it serves a checkpoint function to monitor and modulate meiotic recombination.Project SummaryOur genomes are passed down from one generation to the next through the specialized cell division program of meiosis. Meiosis is highly regulated to coordinate both the large scale chromosomal and fine scale DNA events to ensure fidelity. We analyzed the role of the tumor suppressor BRCA1/BARD1 complex in meiosis in the worm, Caenorhabditis elegans. We find that BRCA1/BARD1 localizes dynamically to the proteinaeous structure that aligns maternal and paternal chromosomes, where it regulates crossover recombination. Although BRCA1/BARD1 mutants have only subtle meiotic defects, we show that this complex plays a critical role in meiotic recombination when meiosis is perturbed. These results highlight the complexity of ensuring accurate transmission of the genome and uncover the requirement for this conserved complex in meiosis. As women carrying BRCA1 mutations with no indication of cancer have fertility defects, our results provide insight into why BRCA1 mutations impact reproductive success.

scholarly journals Prevalence of Germline Mutations in Genes Engaged in DNA Damage Repair by Homologous Recombination in Patients with Triple-Negative and Hereditary Non-Triple-Negative Breast Cancers

PLoS ONE ◽  
2015 ◽  
Vol 10 (6) ◽  
pp. e0130393 ◽  
Author(s):  
Pawel Domagala ◽  
Anna Jakubowska ◽  
Katarzyna Jaworska-Bieniek ◽  
Katarzyna Kaczmarek ◽  
Katarzyna Durda ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Triple Negative ◽  
Dna Damage Repair ◽  
Germline Mutations ◽  
Breast Cancers ◽  
Damage Repair

scholarly journals PARP inhibitor Olaparib overcomes Sorafenib resistance through reshaping the pluripotent transcriptome in hepatocellular carcinoma

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Xiao-Dong Yang ◽  
Fan-En Kong ◽  
Ling Qi ◽  
Jia-Xin Lin ◽  
Qian Yan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dna Damage ◽  
Stem Cell ◽  
Parp Inhibitor ◽  
Dna Damage Repair ◽  
Embryonic Stem ◽  
Hepatic Differentiation ◽  
Sorafenib Treatment ◽  
Damage Repair ◽  
Stem Cell Pluripotency

AbstractHepatocellular carcinoma (HCC) is one of the most common human malignancies worldwide with very poor prognosis. Resistance to targeted therapeutic drugs such as sorafenib remains one of the major challenges in clinical treatment. In the present study, PARP1 was found to be highly expressed in human embryonic stem cells, but progressively decreased upon specified hepatic differentiation. Reactivation of PARP1 expression was also detected in HCC residual tumors after sorafenib treatment in xenograft mouse model, indicating the potential important roles of PARP1 in stem cell pluripotency and HCC sorafenib treatment resistance. Overexpression of PARP1 was frequently observed in HCC patients, and closely associated with poor clinical outcome. Treatment of Sorafenib induced activation of DNA damage repair signaling, which is highly active and essential for maintenance of stem cell pluripotency in HCC residual tumors. PARP inhibitor Olaparib extensively suppressed the DNA damage repair signaling, and significantly inhibited the global pluripotent transcriptional network. The repression of key pluripotent transcriptional factors and DNA damage repair signaling by Olaparib was mainly through CHD1L-mediated condensation of the chromatin structure at their promotor regions. The global reshaping of the pluripotent transcriptome by Olaparib might reinforce Sorafenib in eliminating HCC residual tumors and enhance therapeutic efficiency.

scholarly journals Clinical Impact of Somatic Variants in Homologous Recombination Repair-Related Genes in Ovarian High-Grade Serous Carcinoma

2020 ◽  
Vol 52 (2) ◽  
pp. 634-644 ◽  
Author(s):  
Min Chul Choi ◽  
Sohyun Hwang ◽  
Sewha Kim ◽  
Sang Geun Jung ◽  
Hyun Park ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Parp Inhibitor ◽  
Dna Damage Repair ◽  
Disease Free Survival ◽  
Serous Carcinoma ◽  
High Grade ◽  
Repair Gene ◽  
Damage Repair ◽  
Repair Genes

PurposeIn this study, we investigated the frequencies of mutations in DNA damage repair genes including <i>BRCA1</i>, <i>BRCA2</i>, homologous recombination genes and <i>TP53</i> gene in ovarian high-grade serous carcinoma, alongside those of germline and somatic <i>BRCA</i> mutations, with the aim of improving the identification of patients suitable for treatment with poly(ADP-ribose) polymerase inhibitors.Materials and MethodsTissue samples from 77 Korean patients with ovarian high-grade serous carcinoma were subjected to next-generation sequencing. Pathogenic alterations of 38 DNA damage repair genes and <i>TP53</i> gene and their relationships with patient survival were examined. Additionally, we analyzed <i>BRCA</i> germline variants in blood samples from 47 of the patients for comparison.Results<i>BRCA1</i>, <i>BRCA2</i>, and <i>TP53</i> mutations were detected in 28.6%, 5.2%, and 80.5% of the 77 patients, respectively. Alterations in <i>RAD50, ATR, MSH6, MSH2</i>, and <i>FANCA</i> were also identified. At least one mutation in a DNA damage repair gene was detected in 40.3% of patients (31/77). Germline and somatic <i>BRCA</i> mutations were found in 20 of 47 patients (42.6%), and four patients had only somatic mutations without germline mutations (8.5%, 4/47). Patients with DNA damage repair gene alterations with or without <i>TP53</i>mutation, exhibited better disease-free survival than those with <i>TP53</i> mutation alone.ConclusionDNA damage repair genes were mutated in 40.3% of patients with high-grade serous carcinoma, with somatic <i>BRCA</i> mutations in the absence of germline mutation in 8.5%. Somatic variant examination, along with germline testing of DNA damage repair genes, has potential to detect additional candidates for PARP inhibitor treatment.

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