scholarly journals Deleterious Homologous Recombination Pathway Gene Mutation

2020 ◽  
Author(s):  
Keyword(s):  
Homologous Recombination ◽  
Gene Mutation ◽  
Homologous Recombination Pathway ◽  
Pathway Gene ◽  
Recombination Pathway

scholarly journals Clinical Outcome of Leiomyosarcomas With Somatic Alteration in Homologous Recombination Pathway Genes

2020 ◽  
pp. 1350-1360
Author(s):  
Evan Rosenbaum ◽  
Philip Jonsson ◽  
Kenneth Seier ◽  
Li-Xuan Qin ◽  
Ping Chi ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Clinical Outcome ◽  
Clinical Outcomes ◽  
Univariable Analysis ◽  
Homologous Recombination Pathway ◽  
Gene Alteration ◽  
Pathway Gene ◽  
Recombination Pathway ◽  
Gene Alterations ◽  
Recombination Gene

PURPOSE To detect alterations in DNA damage repair (DDR) genes, measure homologous recombination deficiency (HRD), and correlate these findings with clinical outcome in patients with leiomyosarcoma (LMS). PATIENTS AND METHODS Patients with LMS treated at Memorial Sloan Kettering (MSK) Cancer Center who consented to prospective targeted next-generation sequencing with MSK-IMPACT were screened for oncogenic somatic variants in one of 33 DDR genes; where feasible, an experimental HRD score was calculated from IMPACT data. Progression-free survival (PFS) and overall survival (OS) were estimated after stratifying patients by DDR gene alteration status and HRD score. RESULTS Of 211 patients with LMS, 20% had an oncogenic DDR gene alteration. Univariable analysis of PFS in 117 patients who received standard frontline chemotherapy in the metastatic setting found that an altered homologous recombination pathway gene was significantly associated with shorter PFS (hazard ratio [HR], 1.79; 95% CI, 1.04 to 3.07; P = .035). Non- BRCA homologous recombination gene alteration was associated with shorter PFS (HR, 2.61; 95% CI, 1.35 to 5.04; P = .004) compared with BRCA-altered and wild-type homologous recombination genes. Univariable analysis of OS from diagnosis in the entire cohort of 211 patients found that age, tumor size, number of metastatic sites, localized disease, and non- BRCA homologous recombination gene alteration were significantly associated with OS. On multivariable analysis, non- BRCA homologous recombination pathway gene alteration remained significant (HR, 4.91; 95% CI, 2.47 to 9.76; P < .001). High HRD score was not associated with a different PFS or OS. CONCLUSION Patients with LMS with homologous recombination pathway gene alterations have poor clinical outcomes, particularly those with non- BRCA gene alterations. HRD score calculated from a targeted exome panel did not discern disparate clinical outcomes.

scholarly journals Crystal structure of RecR, a member of the RecFOR DNA-repair pathway, fromPseudomonas aeruginosaPAO1

2018 ◽  
Vol 74 (4) ◽  
pp. 222-230
Author(s):  
Shiyou Che ◽  
Yujing Chen ◽  
Yakun Liang ◽  
Qionglin Zhang ◽  
Mark Bartlam
Keyword(s):  
Crystal Structure ◽  
Dna Damage ◽  
Homologous Recombination ◽  
Analytical Ultracentrifugation ◽  
Repair Process ◽  
Asymmetric Unit ◽  
Homologous Recombination Pathway ◽  
Damage Repair ◽  
Important Regulator ◽  
Recombination Pathway

DNA damage is usually lethal to all organisms. Homologous recombination plays an important role in the DNA damage-repair process in prokaryotic organisms. Two pathways are responsible for homologous recombination inPseudomonas aeruginosa: the RecBCD pathway and the RecFOR pathway. RecR is an important regulator in the RecFOR homologous recombination pathway inP. aeruginosa. It forms complexes with RecF and RecO that can facilitate the loading of RecA onto ssDNA in the RecFOR pathway. Here, the crystal structure of RecR fromP. aeruginosaPAO1 (PaRecR) is reported.PaRecR crystallizes in space groupP6122, with two monomers per asymmetric unit. Analytical ultracentrifugation data show thatPaRecR forms a stable dimer, but can exist as a tetramer in solution. The crystal structure shows that dimericPaRecR forms a ring-like tetramer architectureviacrystal symmetry. The presence of a ligand in the Walker B motif of one RecR subunit suggests a putative nucleotide-binding site.

scholarly journals Increased sensitivity to ionizing radiation by targeting the homologous recombination pathway in glioma initiating cells

2014 ◽  
Vol 8 (8) ◽  
pp. 1603-1615 ◽  
Author(s):  
Yi Chieh Lim ◽  
Tara L. Roberts ◽  
Bryan W. Day ◽  
Brett W. Stringer ◽  
Sergei Kozlov ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Ionizing Radiation ◽  
Homologous Recombination Pathway ◽  
Glioma Initiating Cells ◽  
Increased Sensitivity ◽  
Recombination Pathway

scholarly journals Development of Serous Ovarian Cancer is Associated with the Expression of Homologous Recombination Pathway Proteins

2014 ◽  
Vol 20 (4) ◽  
pp. 931-938 ◽  
Author(s):  
Qingqing Ye ◽  
Li Chen ◽  
Xiaolu Yin ◽  
Yuan Jie Charles Liu ◽  
Qunsheng Ji ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Serous Ovarian Cancer ◽  
Homologous Recombination Pathway ◽  
Recombination Pathway

Ovarian cancer: Status of homologous recombination pathway as a predictor of drug response

2016 ◽  
Vol 101 ◽  
pp. 50-59 ◽  
Author(s):  
Nicolas De Picciotto ◽  
Wulfran Cacheux ◽  
Arnaud Roth ◽  
Pierre O. Chappuis ◽  
S. Intidhar Labidi-Galy
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Drug Response ◽  
Homologous Recombination Pathway ◽  
Recombination Pathway

scholarly journals SMC protein RecN drives translocation and remodelling of RecA filament for homology search

2021 ◽  
Author(s):  
Afroze Chimthanawala ◽  
Jyotsana Parmar ◽  
Sujan Kumar ◽  
Krishnan S Iyer ◽  
Madan Rao ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Search Strategy ◽  
Strand Break ◽  
Homology Search ◽  
Filament Length ◽  
Optimal Search ◽  
Stochastic Description ◽  
Homologous Recombination Pathway ◽  
Search Mechanism ◽  
Recombination Pathway

While the molecular repertoire of the homologous recombination pathway is well studied, the search mechanism that enables recombination between distant homologous regions is poorly understood. Here, we follow the dynamics of the recombinase RecA, an essential component of homology search, after induction of a single double-strand break on the Caulobacter chromosome. We find that the RecA-nucleoprotein filament translocates in a directional manner in the cell, undergoing several pole-to-pole traversals, until homology search is complete. Simultaneously, the filament undergoes dynamic remodelling; both translocation and dynamic remodelling are contingent on the action of the SMC protein RecN via its ATPase cycle. We provide a stochastic description of RecN regulated changes in filament length during translocation via modulation of RecA assembly-disassembly. Together, the observed RecN driven RecA dynamics points to a novel optimal search strategy.

scholarly journals Frequency of Germline Mutations in Cancer Susceptibility Genes in Malignant Mesothelioma

2018 ◽  
Vol 36 (28) ◽  
pp. 2863-2871 ◽  
Author(s):  
Vasiliki Panou ◽  
Meghana Gadiraju ◽  
Arthur Wolin ◽  
Caroline M. Weipert ◽  
Emily Skarda ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Cancer Diagnosis ◽  
Cancer Susceptibility ◽  
Asbestos Exposure ◽  
Germline Mutations ◽  
Susceptibility Genes ◽  
Second Cancer ◽  
Homologous Recombination Pathway ◽  
Cancer Susceptibility Genes ◽  
Recombination Pathway

Purpose The aim of the current study was to determine the prevalence and clinical predictors of germline cancer susceptibility mutations in patients with malignant mesothelioma (MM). Methods We performed targeted capture and next-generation sequencing of 85 cancer susceptibility genes on germline DNA from 198 patients with pleural, peritoneal, and tunica vaginalis MM. Results Twenty-four germline mutations were identified in 13 genes in 23 (12%) of 198 patients. BAP1 mutations were the most common (n = 6; 25%). The remaining were in genes involved in DNA damage sensing and repair (n = 14), oxygen sensing (n = 2), endosome trafficking (n = 1), and cell growth (n = 1). Pleural site (odds ratio [OR], 0.23; 95% CI, 0.10 to 0.58; P < .01), asbestos exposure (OR, 0.28; 95% CI, 0.11 to 0.72; P < .01), and older age (OR, 0.95; 95% CI, 0.92 to 0.99; P = .01) were associated with decreased odds of carrying a germline mutation, whereas having a second cancer diagnosis (OR, 3.33; 95% CI, 1.22 to 9.07; P = .02) significantly increased the odds. The odds of carrying a mutation in BAP1 (OR, 1,658; 95% CI, 199 to 76,224; P < .001), BRCA2 (OR, 5; 95% CI, 1.0 to 14.7; P = .03), CDKN2A (OR, 53; 95% CI, 6 to 249; P < .001), TMEM127 (OR, 88; 95% CI, 1.7 to 1,105; P = .01), VHL (OR, 51; 95% CI, 1.1 to 453; P = .02), and WT1 (OR, 20; 95% CI, 0.5 to 135; P = .049) were significantly higher in MM cases than in a noncancer control population. Tumor sequencing identified mutations in a homologous recombination pathway gene in 52% (n = 29 of 54). Conclusion A significant proportion of patients with MM carry germline mutations in cancer susceptibility genes, especially those with peritoneal MM, minimal asbestos exposure, young age, and a second cancer diagnosis. These data support clinical germline genetic testing for patients with MM and provide a rationale for additional investigation of the homologous recombination pathway in MM.

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