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 Inhibitory effect of uranyl nitrate on DNA double-strand break repair by depression of a set of proteins in the homologous recombination pathway

2017 ◽  
Vol 6 (5) ◽  
pp. 711-718 ◽  
Author(s):  
Feng Jin ◽  
Teng Ma ◽  
Hua Guan ◽  
Zhi-Hua Yang ◽  
Xiao-Dan Liu ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Environmental Exposure ◽  
Uranyl Nitrate ◽  
Tissue Injury ◽  
Strand Break ◽  
Inhibitory Effect ◽  
Homologous Recombination Pathway ◽  
Dna Double Strand Break ◽  
Occupational And Environmental Exposure ◽  
Recombination Pathway

Occupational and environmental exposure to uranium has been confirmed to cause tissue injury and carcinogenesis.

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 RBX1 prompts degradation of EXO1 to limit the homologous recombination pathway of DNA double-strand break repair in G1 phase

2019 ◽  
Vol 27 (4) ◽  
pp. 1383-1397 ◽  
Author(s):  
Ying Xie ◽  
Yi-Ke Liu ◽  
Zong-Pei Guo ◽  
Hua Guan ◽  
Xiao-Dan Liu ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Strand Break ◽  
Expression Level ◽  
G1 Phase ◽  
Dna Double Strand Breaks ◽  
Dsb Repair ◽  
Elevated Expression ◽  
Recombination Pathway ◽  
Specific Degradation ◽  
End Resection

Abstract End resection of DNA double-strand breaks (DSBs) to form 3′ single-strand DNA (ssDNA) is critical to initiate the homologous recombination (HR) pathway of DSB repair. HR pathway is strictly limited in the G1-phase cells because of lack of homologous DNA as the templates. Exonuclease 1 (EXO1) is the key molecule responsible for 3′ ssDNA formation of DSB end resection. We revealed that EXO1 is inactivated in G1-phase cells via ubiquitination-mediated degradation, resulting from an elevated expression level of RING-box protein 1 (RBX1) in G1 phase. The increased RBX1 significantly prompted the neddylation of Cullin1 and contributed to the G1 phase-specific degradation of EXO1. Knockdown of RBX1 remarkedly attenuated the degradation of EXO1 and increased the end resection and HR activity in γ-irradiated G1-phase cells, as demonstrated by the increased formation of RPA32, BrdU, and RAD51 foci. And EXO1 depletion mitigated DNA repair defects due to RBX1 reduction. Moreover, increased autophosphorylation of DNA-PKcs at S2056 was found to be responsible for the higher expression level of the RBX1 in the G1 phase. Inactivation of DNA-PKcs decreased RBX1 expression, and simultaneously increased EXO1 expression and DSB end resection in G1-phase cells. This study demonstrates a new mechanism for restraining the HR pathway of DNA DSB repair in G1 phase via RBX1-prompted inactivation of EXO1.

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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