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Modulating mutational outcomes and improving precise gene editing at CRISPR-Cas9-induced breaks by chemical inhibition of end-joining pathways.
Schimmel J, Muñoz-Subirana N, Kool H, van Schendel R, van der Vlies S, Kamp JA, de Vrij FMS, Kushner SA, Smith GCM, Boulton SJ, Tijsterman M. Schimmel J, et al. Cell Rep. 2023 Feb 28;42(2):112019. doi: 10.1016/j.celrep.2023.112019. Epub 2023 Jan 25. Cell Rep. 2023. PMID: 36701230 Free article.
We show robust inhibition of TMEJ activity at CRISPR-Cas9-induced double-strand breaks (DSBs) using ART558, a potent polymerase theta (Pol) inhibitor. ...Conversely, NHEJ deficiency triggers the formation of large kb-sized deletions, which we show are the products of mutag …
We show robust inhibition of TMEJ activity at CRISPR-Cas9-induced double-strand breaks (DSBs) using ART558, a potent polymerase theta …
BRCA1-associated structural variations are a consequence of polymerase theta-mediated end-joining.
Kamp JA, van Schendel R, Dilweg IW, Tijsterman M. Kamp JA, et al. Nat Commun. 2020 Jul 17;11(1):3615. doi: 10.1038/s41467-020-17455-3. Nat Commun. 2020. PMID: 32680986 Free PMC article.
We here show that the mutational landscape of BRCA1 deficiency in C. elegans closely resembles that of BRCA1-deficient tumours. We identify polymerase theta-mediated end-joining (TMEJ) to be responsible: knocking out polq-1 suppresses the accumulation of deletions a …
We here show that the mutational landscape of BRCA1 deficiency in C. elegans closely resembles that of BRCA1-deficient tumours. We id …
Meiotic Double-Strand Break Proteins Influence Repair Pathway Utilization.
Macaisne N, Kessler Z, Yanowitz JL. Macaisne N, et al. Genetics. 2018 Nov;210(3):843-856. doi: 10.1534/genetics.118.301402. Epub 2018 Sep 21. Genetics. 2018. PMID: 30242011 Free PMC article.
Our investigations reveal that nonhomologous and theta-mediated end joining (c-NHEJ and TMEJ, respectively) and single strand annealing (SSA) function redundantly to repair DSBs when HR is compromised, and that HIM-5 influences the utilization of TMEJ and SSA …
Our investigations reveal that nonhomologous and theta-mediated end joining (c-NHEJ and TMEJ, respectively) and single strand …
Combined loss of three DNA damage response pathways renders C. elegans intolerant to light.
van Bostelen I, Tijsterman M. van Bostelen I, et al. DNA Repair (Amst). 2017 Jun;54:55-62. doi: 10.1016/j.dnarep.2017.04.002. Epub 2017 Apr 14. DNA Repair (Amst). 2017. PMID: 28472716
Yet, we observe an unprecedented synergistic relationship when these pathways are inactivated in combination. C. elegans mutants that lack nucleotide excision repair (NER), translesion synthesis (TLS) and alternative end joining (altEJ) grow undisturbed in the dark, but be …
Yet, we observe an unprecedented synergistic relationship when these pathways are inactivated in combination. C. elegans mutants that …
Turning end-joining upside down in mitosis.
Llorens-Agost M, Ensminger M, Le HP, Heyer WD, Löbrich M. Llorens-Agost M, et al. Mol Cell Oncol. 2021 Nov 23;8(6):2007029. doi: 10.1080/23723556.2021.2007029. eCollection 2021. Mol Cell Oncol. 2021. PMID: 35419469 Free PMC article.
Helicase Q promotes homology-driven DNA double-strand break repair and prevents tandem duplications.
Kamp JA, Lemmens BBLG, Romeijn RJ, Changoer SC, van Schendel R, Tijsterman M. Kamp JA, et al. Nat Commun. 2021 Dec 8;12(1):7126. doi: 10.1038/s41467-021-27408-z. Nat Commun. 2021. PMID: 34880204 Free PMC article.
In addition to high fidelity repair, three intrinsically mutagenic DNA break repair routes have been described, i.e. single-strand annealing (SSA), polymerase theta-mediated end-joining (TMEJ) and residual ill-defined microhomology-mediated end-joining (MMEJ) activity. Her …
In addition to high fidelity repair, three intrinsically mutagenic DNA break repair routes have been described, i.e. single-strand annealing …
Polymerase theta-mediated end joining of replication-associated DNA breaks in C. elegans.
Roerink SF, van Schendel R, Tijsterman M. Roerink SF, et al. Genome Res. 2014 Jun;24(6):954-62. doi: 10.1101/gr.170431.113. Epub 2014 Mar 10. Genome Res. 2014. PMID: 24614976 Free PMC article.
Here, through whole-genome sequencing of animal populations that were clonally propagated for more than 50 generations, we identify a distinct class of deletions that spontaneously accumulate in C. elegans strains lacking translesion synthesis (TLS) polymerases. ...This pa …
Here, through whole-genome sequencing of animal populations that were clonally propagated for more than 50 generations, we identify a distin …
Translesion synthesis polymerases are dispensable for C. elegans reproduction but suppress genome scarring by polymerase theta-mediated end joining.
van Bostelen I, van Schendel R, Romeijn R, Tijsterman M. van Bostelen I, et al. PLoS Genet. 2020 Apr 24;16(4):e1008759. doi: 10.1371/journal.pgen.1008759. eCollection 2020 Apr. PLoS Genet. 2020. PMID: 32330130 Free PMC article.
These scars, which are the product of polymerase theta-mediated end joining (TMEJ), are found overrepresented at guanine bases, consistent with TLS suppressing DNA double-strand breaks (DSBs) from occurring at replication-blocking guanine adducts. We found that in C
These scars, which are the product of polymerase theta-mediated end joining (TMEJ), are found overrepresented at guanine bases, consi …
Genomic Scars Generated by Polymerase Theta Reveal the Versatile Mechanism of Alternative End-Joining.
van Schendel R, van Heteren J, Welten R, Tijsterman M. van Schendel R, et al. PLoS Genet. 2016 Oct 18;12(10):e1006368. doi: 10.1371/journal.pgen.1006368. eCollection 2016 Oct. PLoS Genet. 2016. PMID: 27755535 Free PMC article.
Here, we demonstrate for two of the most widely used mutagens, i.e. ethyl methanesulfonate (EMS) and photo-activated trimethylpsoralen (UV/TMP), that deletion mutagenesis is the result of polymerase Theta (POLQ)-mediated end joining (TMEJ) of double strand breaks (DSBs). T …
Here, we demonstrate for two of the most widely used mutagens, i.e. ethyl methanesulfonate (EMS) and photo-activated trimethylpsoralen (UV/T …
Improved Constraints on Sterile Neutrino Mixing from Disappearance Searches in the MINOS, MINOS+, Daya Bay, and Bugey-3 Experiments.
Adamson P, An FP, Anghel I, Aurisano A, Balantekin AB, Band HR, Barr G, Bishai M, Blake A, Blyth S, Cao GF, Cao J, Cao SV, Carroll TJ, Castromonte CM, Chang JF, Chang Y, Chen HS, Chen R, Chen SM, Chen Y, Chen YX, Cheng J, Cheng ZK, Cherwinka JJ, Childress S, Chu MC, Chukanov A, Coelho JAB, Cummings JP, Dash N, De Rijck S, Deng FS, Ding YY, Diwan MV, Dohnal T, Dolzhikov D, Dove J, Dvořák M, Dwyer DA, Evans JJ, Feldman GJ, Flanagan W, Gabrielyan M, Gallo JP, Germani S, Gomes RA, Gonchar M, Gong GH, Gong H, Gouffon P, Graf N, Grzelak K, Gu WQ, Guo JY, Guo L, Guo XH, Guo YH, Guo Z, Habig A, Hackenburg RW, Hahn SR, Hans S, Hartnell J, Hatcher R, He M, Heeger KM, Heng YK, Higuera A, Holin A, Hor YK, Hsiung YB, Hu BZ, Hu JR, Hu T, Hu ZJ, Huang HX, Huang J, Huang XT, Huang YB, Huber P, Jaffe DE, Jen KL, Ji XL, Ji XP, Johnson RA, Jones D, Kang L, Kettell SH, Koerner LW, Kohn S, Kordosky M, Kramer M, Kreymer A, Lang K, Langford TJ, Lee J, Lee JHC, Lei RT, Leitner R, Leung JKC, Li F, Li HL, Li JJ, Li QJ, Li S, Li SC, Li SJ, Li WD, Li XN, Li XQ, Li YF, Li ZB, Liang H, Lin CJ, Lin GL, Lin S, Ling JJ, Link JM, Littenberg L, Littlejohn BR, Liu JC, Liu JL, Liu Y, Liu YH, Lu C, Lu HQ, Lu JS, Lucas… See abstract for full author list ➔ Adamson P, et al. Phys Rev Lett. 2020 Aug 14;125(7):071801. doi: 10.1103/PhysRevLett.125.071801. Phys Rev Lett. 2020. PMID: 32857527
Significantly improved constraints on the teta_{mue} mixing angle are derived that constitute the most constraining limits to date over five orders of magnitude in the mass-squared splitting deltam_{41}^{2}, excluding the 90% C.L. sterile-neutrino parameter space allowed b …
Significantly improved constraints on the teta_{mue} mixing angle are derived that constitute the most constraining limits to date over five …