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91.
92.
Mutational signatures of non‐homologous and polymerase theta‐mediated end‐joining in embryonic stem cells
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Joost Schimmel Hanneke Kool Robin van Schendel Marcel Tijsterman 《The EMBO journal》2017,36(24):3634-3649
Cells employ potentially mutagenic DNA repair mechanisms to avoid the detrimental effects of chromosome breaks on cell survival. While classical non‐homologous end‐joining (cNHEJ) is largely error‐free, alternative end‐joining pathways have been described that are intrinsically mutagenic. Which end‐joining mechanisms operate in germ and embryonic cells and thus contribute to heritable mutations found in congenital diseases is, however, still largely elusive. Here, we determined the genetic requirements for the repair of CRISPR/Cas9‐induced chromosomal breaks of different configurations, and establish the mutational consequences. We find that cNHEJ and polymerase theta‐mediated end‐joining (TMEJ) act both parallel and redundant in mouse embryonic stem cells and account for virtually all end‐joining activity. Surprisingly, mutagenic repair by polymerase theta (Pol θ, encoded by the Polq gene) is most prevalent for blunt double‐strand breaks (DSBs), while cNHEJ dictates mutagenic repair of DSBs with protruding ends, in which the cNHEJ polymerases lambda and mu play minor roles. We conclude that cNHEJ‐dependent repair of DSBs with protruding ends can explain de novo formation of tandem duplications in mammalian genomes. 相似文献
93.
《DNA Repair》2017
The detection of γ-H2AX focus is one of the most sensitive ways to monitor DNA double-strand breaks (DSBs). Although changes in γ-H2AX activity have been studied in tumor cells in colorectal cancer (CRC), changes in peripheral blood lymphocytes (PBLs) have not been examined previously. We hypothesize that higher levels of irradiation-induced γ-H2AX in PBLs may be associated with an elevated risk of colorectal cancer (CRC). In a case-control study, the baseline and ionizing radiation (IR)-induced γ-H2AX levels in PBLs from frequency-matched 320 untreated CRC patients and 320 controls were detected by a laser scanning cytometer-based immunocytochemical method. We used unconditional multivariable logistic regression to evaluate CRC risk by using the ratio of IR-induced γ-H2AX to the baseline levels with adjustment of age, sex and smoking status. We found CRC cases had significantly higher γ-H2AX ratio (1.5 vs. 1.41, P < 0.0001) compared with controls. When using the median γ-H2AX ratio of controls as a cutoff point, we found higher γ-H2AX ratio was significantly associated with an increased risk of CRC (OR = 6.72, 95% CI = 4.54–9.94). Quartile analyses also showed significant dose–response relationship between higher γ-H2AX ratio and increased risk of CRC (P for trend < 0.0001). Age, sex, BMI and smoking status also influenced the association of γ-H2AX ratio with CRC risk; however, no interactions with γ-H2AX ratio were observed. These results support the premise that DSBs in peripheral blood as measured by γ-H2AX level might represent an intermediate phenotype to assess the risk of CRC. Future prospective studies are necessary to confirm our findings in independent populations. 相似文献
94.
Unnikrishnan Sivadasan Tendry Randriamanana Cao Chenhao Virpi Virjamo Line Nybakken Riitta Julkunen‐Tiitto 《Ecology and evolution》2017,7(19):7998-8007
Boreal tree species are excellent tools for studying tolerance to climate change. Bud phenology is a trait, which is highly sensitive to environmental fluctuations and thus useful for climate change investigations. However, experimental studies of bud phenology under simulated climate change outdoors are deficient. We conducted a multifactorial field experiment with single (T, UVA, UVB) and combined treatments (UVA+T, UVB+T) of elevated temperature (T, +2°C) and ultraviolet‐B radiation (+30% UVB) in order to examine their impact on both male and female genotypes of aspen (Populus tremula L.). This study focuses on the effect of the treatments in years 2 and 3 after planting (2013, 2014) and follows how bud phenology is adapting in year 4 (2015), when the treatments were discontinued. Moreover, the effect of bud removal was recorded. We found that elevated temperature played a key role in delaying bud set and forcing bud break in intact individuals, as well as slightly delaying bud break in bud‐removed individuals. UVB delayed the bud break in bud‐removed males. In addition, both UVA and UVB interacted with temperature in year 3 and even in year 4, when the treatments were off, but only in male individuals. Axillary bud removal forced both bud break and bud set under combined treatments (UVA+T, UVB+T) and delayed both under individual treatments (T, UVB). In conclusion, male aspens were more responsive to the treatments than females and that effect of elevated temperature and UV radiation on bud set and bud break of aspen is not disappearing over 4‐year study period. 相似文献
95.
紫斑牡丹休眠地下芽在组织培养条件下的发育研究 总被引:9,自引:0,他引:9
以紫斑牡丹(Paeonia rockii T.Hong et Li J.J.)休眠地下芽为材料,对同一时期打破休眠的地下芽在3种不同培养基上的发育状况、不同时间低温处理后在同一培养基上的发育,以及不同时期休眠地下芽在同一培养条件下的发育进行了比较研究。结果表明:MS+BA 1mg/L NAA 0.5mg/L 2,4-d 0.5mg/L最有利于打破休眠的地下芽发育;不同低温处理对休眠地下芽的萌发率及发育速率作用明显不同,其中,720h的低温处理效果最佳;彻底打破休眠的不同时期地下芽在同一培养条件下发育速率基本一致。 相似文献
96.
Spring 2007 warmth and frost: phenology, damage and refoliation in a temperate deciduous forest 总被引:2,自引:0,他引:2
Carol K. Augspurger 《Functional ecology》2009,23(6):1031-1039
97.
Kazutsune Yamagata Issay Kitabayashi 《Biochemical and biophysical research communications》2009,390(4):1355-596
Sirt1 appear to be NAD(+)-dependent deacetylase that deacetylates histones and several non-histone proteins. In this study, we identified Sirt1 as a physical interaction partner of Tip60, which is a mammalian MYST-type histone acetyl-transferase that specifically acetylates histones H2A and H4. Although Tip60 also acetylates DNA damage-specific histone H2A variant H2AX in response to DNA damage, which is a process required for appropriate DNA damage response, overexpression of Sirt1 represses Tip60-mediated acetylation of H2AX. Furthermore, Sirt1 depletion by RNAi causes excessive acetylation of H2AX, and enhances accumulation of γ-ray irradiation-induced MDC1, BRCA1, and Rad51 foci in nuclei. These findings suggest that Sirt1 functions as negative regulator of Tip60-mediated acetylation of H2AX. Moreover, Sirt1 deacetylates an acetylated Tip60 in response to DNA damage and stimulates proteasome-dependent Tip60 degradation in vivo, suggesting that Sirt1 negatively regulates the protein level of Tip60 in vivo. Sirt1 may thus repress excessive activation of the DNA damage response and Rad51-homologous recombination repair by suppressing the function of Tip60. 相似文献
98.
99.
Rad51, Rad52, and replication protein-A (RPA) play crucial roles in the repair of DNA double-strand breaks in Saccharomyces cerevisiae. Rad51 mediates DNA strand exchange, a key reaction in DNA recombination. Rad52 recruits Rad51 into single-stranded DNAs (ssDNAs) that are saturated with RPA. Rad52 also promotes annealing of ssDNA strands that are complexed with RPA. Specific protein-protein interactions are involved in these reactions. Here we report new biochemical characteristics of these protein interactions. First, Rad52-RPA interaction requires multiple molecules of RPA to be associated with ssDNA, suggesting that multiple contacts between the Rad52 ring and RPA-ssDNA filament are needed for stable binding. Second, RPA-t11, which is a recombination-deficient mutant of RPA, displays a defect in interacting with Rad52 in the presence of salt above 50 mM, explaining the defect in Rad52-mediated ssDNA annealing in the presence of this mutation. Third, ssDNA annealing promoted by Rad52 is preceded by aggregation of multiple RPA-ssDNA complexes with Rad52, and Rad51 inhibits this aggregation. These results suggest a regulatory role for Rad51 that suppresses ssDNA annealing and facilitates DNA strand invasion. Finally, the Rad51-double-stranded DNA complex disrupts Rad52-RPA interaction in ssDNA and titrates Rad52 from RPA. This suggests an additional regulatory role for Rad51 following DNA strand invasion, where Rad51-double-stranded DNA may inhibit illegitimate second-end capture to ensure the error-free repair of a DNA double-strand break. 相似文献
100.
The BRCA2 tumour suppressor regulates the RAD-51 recombinase during double-strand break (DSB) repair by homologous recombination (HR) but how BRCA2 executes its functions is not well understood. We previously described a functional homologue of BRCA2 in Caenorhabditis elegans (CeBRC-2) that binds preferentially to single-stranded DNA via an OB-fold domain and associates directly with RAD-51 via a single BRC domain. Consistent with a direct role in HR, Cebrc-2 mutants are defective for repair of meiotic and radiation-induced DSBs due to an inability to regulate RAD-51. Here, we explore the function of CeBRC-2 in HR processes using purified proteins. We show that CeBRC-2 stimulates RAD-51-mediated D-loop formation and reduces the rate of ATP hydrolysis catalysed by RAD-51. These functions of CeBRC-2 are dependent upon direct association with RAD-51 via its BRC motif and on its DNA-binding activity, as point mutations in the BRC domain that abolish RAD-51 binding or the BRC domain of CeBRC-2 alone, lacking the DNA-binding domain, fail to stimulate RAD-51-mediated D-loop formation and do not reduce the rate of ATP hydrolysis by RAD-51. Phenotypic comparison of Cebrc-2 and rad-51 mutants also revealed a role for CeBRC-2 in an error-prone DSB repair pathway independent of rad-51 and non-homologous end joining, raising the possibility that CeBRC-2 may have replaced the role of vertebrate Rad52 in DNA single-strand annealing (SSA), which is missing from C. elegans. Indeed, we show here that CeBRC-2 mediates SSA of RPA-oligonucleotide complexes similar to Rad52. These results reveal RAD-51-dependent and -independent functions of CeBRC-2 that provide an explanation for the difference in DNA repair defects observed in Cebrc-2 and rad-51 mutants, and define mechanistic roles for CeBRC-2 in HR and in the SSA pathway for DSB repair. 相似文献