Browsing by Subject "DNA helicases"

Now showing 1 - 2 of 2
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    De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders
    (American Association for the Advancement of Science, 2022) Jia, Xiangbin; Zhang, Shujie; Tan, Senwei; Du, Bing; He, Mei; Qin, Haisong; Chen, Jia; Duan, Xinyu; Luo, Jingsi; Chen, Fei; Ouyang, Luping; Wang, Jian; Chen, Guodong; Yu, Bin; Zhang, Ge; Zhang, Zimin; Lyu, Yongqing; Huang, Yi; Jiao, Jian; Chen, Jin Yun (Helen); Swoboda, Kathryn J.; Agolini, Emanuele; Novelli, Antonio; Leoni, Chiara; Zampino, Giuseppe; Cappuccio, Gerarda; Brunetti-Pierri, Nicola; Gerard, Benedicte; Ginglinger, Emmanuelle; Richer, Julie; McMillan, Hugh; White-Brown, Alexandre; Hoekzema, Kendra; Bernier, Raphael A.; Kurtz-Nelson, Evangeline C.; Earl, Rachel K.; Meddens, Claartje; Alders, Marielle; Fuchs, Meredith; Caumes, Roseline; Brunelle, Perrine; Smol, Thomas; Kuehl, Ryan; Day-Salvatore, Debra-Lynn; Monaghan, Kristin G.; Morrow, Michelle M.; Eichler, Evan E.; Hu, Zhengmao; Yuan, Ling; Tan, Jieqiong; Xia, Kun; Shen, Yiping; Guo, Hui; Pediatrics, School of Medicine
    Stress granules (SGs) are cytoplasmic assemblies in response to a variety of stressors. We report a new neurodevelopmental disorder (NDD) with common features of language problems, intellectual disability, and behavioral issues caused by de novo likely gene-disruptive variants in UBAP2L, which encodes an essential regulator of SG assembly. Ubap2l haploinsufficiency in mouse led to social and cognitive impairments accompanied by disrupted neurogenesis and reduced SG formation during early brain development. On the basis of data from 40,853 individuals with NDDs, we report a nominally significant excess of de novo variants within 29 genes that are not implicated in NDDs, including 3 essential genes (G3BP1, G3BP2, and UBAP2L) in the core SG interaction network. We validated that NDD-related de novo variants in newly implicated and known NDD genes, such as CAPRIN1, disrupt the interaction of the core SG network and interfere with SG formation. Together, our findings suggest the common SG pathology in NDDs.
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    Pif1 helicase and Polδ promote recombination-coupled DNA synthesis via bubble migration
    (Springer Nature, 2013) Wilson, Marenda A.; Kwon, YoungHo; Xu, Yuanyuan; Chung, Woo-Hyun; Chi, Peter; Niu, Hengyao; Mayle, Ryan; Chen, Xuefeng; Malkova, Anna; Sung, Patrick; Ira, Grzegorz; Biology, School of Science
    During DNA repair by homologous recombination (HR), DNA synthesis copies information from a template DNA molecule. Multiple DNA polymerases have been implicated in repair-specific DNA synthesis, but it has remained unclear whether a DNA helicase is involved in this reaction. A good candidate DNA helicase is Pif1, an evolutionarily conserved helicase in Saccharomyces cerevisiae important for break-induced replication (BIR) as well as HR-dependent telomere maintenance in the absence of telomerase found in 10-15% of all cancers. Pif1 has a role in DNA synthesis across hard-to-replicate sites and in lagging-strand synthesis with polymerase δ (Polδ). Here we provide evidence that Pif1 stimulates DNA synthesis during BIR and crossover recombination. The initial steps of BIR occur normally in Pif1-deficient cells, but Polδ recruitment and DNA synthesis are decreased, resulting in premature resolution of DNA intermediates into half-crossovers. Purified Pif1 protein strongly stimulates Polδ-mediated DNA synthesis from a D-loop made by the Rad51 recombinase. Notably, Pif1 liberates the newly synthesized strand to prevent the accumulation of topological constraint and to facilitate extensive DNA synthesis via the establishment of a migrating D-loop structure. Our results uncover a novel function of Pif1 and provide insights into the mechanism of HR.