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Dive into the research topics where Jacob G. Jansen is active.

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Featured researches published by Jacob G. Jansen.


Journal of Experimental Medicine | 2006

Strand-biased defect in C/G transversions in hypermutating immunoglobulin genes in Rev1-deficient mice

Jacob G. Jansen; Petra Langerak; Anastasia Tsaalbi-Shtylik; Paul C.M. van den Berk; Heinz Jacobs; Niels de Wind

Somatic hypermutation of Ig genes enables B cells of the germinal center to generate high-affinity immunoglobulin variants. Key intermediates in somatic hypermutation are deoxyuridine lesions, introduced by activation-induced cytidine deaminase. These lesions can be processed further to abasic sites by uracil DNA glycosylase. Mutagenic replication of deoxyuridine, or of its abasic derivative, by translesion synthesis polymerases is hypothesized to underlie somatic hypermutation. Rev1 is a translesion synthesis polymerase that in vitro incorporates uniquely deoxycytidine opposite deoxyuridine and abasic residues. To investigate a role of Rev1 in mammalian somatic hypermutation we have generated mice deficient for Rev1. Although Rev1−/− mice display transient growth retardation, proliferation of Rev1−/− LPS-stimulated B cells is indistinguishable from wild-type cells. In mutated Ig genes from Rev1−/− mice, C to G transversions were virtually absent in the nontranscribed (coding) strand and reduced in the transcribed strand. This defect is associated with an increase of A to T, C to A, and T to C substitutions. These results indicate that Rev1 incorporates deoxycytidine residues, most likely opposite abasic nucleotides, during somatic hypermutation. In addition, loss of Rev1 causes compensatory increase in mutagenesis by other translesion synthesis polymerases.


Molecular and Cellular Biology | 1998

Alkylpurine–DNA–N-Glycosylase Knockout Mice Show Increased Susceptibility to Induction of Mutations by Methyl Methanesulfonate

Rhoderick H. Elder; Jacob G. Jansen; Robert J. Weeks; Mark Andrew Willington; Bryan Deans; Amanda J. Watson; Kurt J. Mynett; John A. Bailey; Donald P. Cooper; Joseph A Rafferty; Mel C. Heeran; Susan W.P. Wijnhoven; Albert A. van Zeeland; Geoffrey P. Margison

ABSTRACT Alkylpurine-DNA-N-glycosylase (APNG) null mice have been generated by homologous recombination in embryonic stem cells. The null status of the animals was confirmed at the mRNA level by reverse transcription-PCR and by the inability of cell extracts of tissues from the knockout (ko) animals to release 3-methyladenine (3-meA) or 7-methylguanine (7-meG) from 3H-methylated calf thymus DNA in vitro. Following treatment with DNA-methylating agents, increased persistence of 7-meG was found in liver sections of APNG ko mice in comparison with wild-type (wt) mice, demonstrating an in vivo phenotype for the APNG null animals. Unlike other null mutants of the base excision repair pathway, the APNG ko mice exhibit a very mild phenotype, show no outward abnormalities, are fertile, and have an apparently normal life span. Neither a difference in the number of leukocytes in peripheral blood nor a difference in the number of bone marrow polychromatic erythrocytes was found when ko and wt mice were exposed to methylating or chloroethylating agents. These agents also showed similar growth-inhibitory effects in primary embryonic fibroblasts isolated from ko and wt mice. However, treatment with methyl methanesulfonate resulted in three- to fourfold more hprt mutations in splenic T lymphocytes from APNG ko mice than in those from wt mice. These mutations were predominantly single-base-pair changes; in the ko mice, they consisted primarily of AT→TA and GC→TA transversions, which most likely are caused by 3-meA and 3- or 7-meG, respectively. These results clearly show an important role for APNG in attenuating the mutagenic effects ofN-alkylpurines in vivo.


Molecular and Cellular Biology | 2009

Separate domains of Rev1 mediate two modes of DNA damage bypass in mammalian cells.

Jacob G. Jansen; Anastasia Tsaalbi-Shtylik; Giel Hendriks; Himabindu Gali; Ayal Hendel; Fredrik Johansson; Klaus Erixon; Zvi Livneh; L.H.F. Mullenders; Lajos Haracska; Niels de Wind

ABSTRACT The Y family DNA polymerase Rev1 has been proposed to play a regulatory role in the replication of damaged templates. To elucidate the mechanism by which Rev1 promotes DNA damage bypass, we have analyzed the progression of replication on UV light-damaged DNA in mouse embryonic fibroblasts that contain a defined deletion in the N-terminal BRCT domain of Rev1 or that are deficient for Rev1. We provide evidence that Rev1 plays a coordinating role in two modes of DNA damage bypass, i.e., an early and a late pathway. The cells carrying the deletion in the BRCT domain are deficient for the early pathway, reflecting a role of the BRCT domain of Rev1 in mutagenic translesion synthesis. Rev1-deficient cells display a defect in both modes of DNA damage bypass. Despite the persistent defect in the late replicational bypass of fork-blocking (6-4)pyrimidine-pyrimidone photoproducts, overall replication is not strongly affected by Rev1 deficiency. This results in almost completely replicated templates that contain gaps encompassing the photoproducts. These gaps are inducers of DNA damage signaling leading to an irreversible G2 arrest. Our results corroborate a model in which Rev1-mediated DNA damage bypass at postreplicative gaps quenches irreversible DNA damage responses.


DNA Repair | 2009

Mammalian polymerase ζ is essential for post-replication repair of UV-induced DNA lesions

Jacob G. Jansen; Anastasia Tsaalbi-Shtylik; Giel Hendriks; Johan Wa Verspuy; Himabindu Gali; Lajos Haracska; Niels de Wind

DNA polymerase zeta is believed to be an essential constituent of DNA damage tolerance, comprising several pathways that allow the replication of DNA templates containing unrepaired damage. We wanted to better define the role of polymerase zeta in DNA damage tolerance in mammalian cells. To this aim we have investigated replication of ultraviolet light-damaged DNA templates in mouse embryonic fibroblasts deficient for Rev3, the catalytic subunit of polymerase zeta. We found that Rev3 is important for a post-replication repair pathway of helix-distorting [6-4]pyrimidine-pyrimidone photoproducts and, to a lesser extent, of cyclobutane pyrimidine dimers. Unlike its partner Rev1, Rev3 appears not to be involved in an immediate translesion synthesis pathway at a stalled replication fork. The deficiency of Rev3(-/-) MEFs in post-replication repair of different photoproducts contributes to the extreme sensitivity of these cells to UV light.


Inorganica Chimica Acta | 1993

Synthesis, characterization, crystal structures and magnetic properties of di- and polynuclear bis(μ-3-pyridin-2-yl-1,2,4- triazolato)copper(II) compounds containing N-methylimidazole, pyrazole or 4,4′-bipyridine as co-ligands

Petie M. Slangen; Petra J. van Koningsbruggen; Jaap G. Haasnoot; Jacob G. Jansen; Syb Gorter; Jan Reedijk; Huub Kooijman; Wilberth J. J. Smeets; Anthony L. Spek

A group of new compounds 1–5 of general formula [Cu2(pt)2L2(NO3)2(H2O)2](H2O)n, with n=1, 2, 3 or 4 and L=N-methylimidazole, pyrazole, 4,4′-bipyridine, H2O and N-butylimidazole, has been prepared and characterized spectroscopically and structurally. The synthesis, characterization, spectral and magnetic properties as well as crystal and molecular structures of [bis(μ-3-pyridin-2-yl-1,2,4-triazolato-N′,N1,N2)]-bis[(1-methylimidazole-N3)(nitrato)(aqua)copper(II)] tetrahydrate, ([Cu2(pt)2(Meim)2(NO3)2(H2O)2](H2O4)4 (1), in which pt=3-pyridin-2-yl-1,2,4-triazolato and Meim=N-methylimidazole, [bis(μ-3-pyridin-2-yl-1,2,4-triazolato-N′,N1,N2)]-bis[(pyrazole-N1)(nitrato)(aqua)copper(II)], [Cu2(pt)2(Hpz)2(NO3)2(H2O)2] (2) in which Hpz=pyrazole, and an unusual chain of dimers, catena-(μ-4,4′-bipyridine)[bis(μ-3-pyridin-2-yl-1,2,4-triazolato-N′N1N2)(nitrato)(aqua)copper(II))], [Cu2(pt)2(4,4′-bpy)(NO3)(H2O)2](NO3)(H2O)4 (3) in which 4,4′-bpy=4,4′-bipyridine, have been studied Crystal structure data are as follows. 1: Cu2N14C22H34O12, T=293 K, triclinic, space group P, with a=9.2685(6), b=9.6897(6), c=10.2313(4) A, α=108.700(4), β=97.884(4), γ=95.396(5)°, Z=1 and V=852.75(8) A3. The least-squares refinement based on 2111 significant reflections (I>2σ(I) converged to R=0.0411 and Rw=0.0446. 2: Cu2N14C20H22O8, T=298 K, monoclinic, space group P21/c, with a=10.812(1), b=13.750(1), c=10.003(1) A, β=113.94(1)°, Z=2 and V=1359.1(2) A3. The least-squares refinement based on 1863 significant reflections (I>2.5σ(I)) converged to R=0.0522 and Rw=0.0485. 3: Cu2N12C24H30O12, T=295 K, monoclinic, space group P21/c, with a=8.8802(11), b=12.9975(8), c=28.7208(19) A, β=92.970(7)°, Z=4 and V=3310.5(5) A3. The least-squares refinement based on 5100 significant reflections (I>2σ(I)) converged to R=0.056 and Rw=0.051. The structures of 1, 2 and 3 consist of dinuclear units, in which the copper(II) ions are linked by two via N(1), N(2) bridging dehydronated Hpt ligands in the equatorial plane. CuN distances vary from 1.970(3) to 1.988(3) A. All copper(II) ions are in a distorted octahedral environment, of which the equatorial plane around the copper atoms is formed by three donor atoms of the pt ligand and one donor atom of another ligand (Meim, Hpz or 4,4′-bpy). A water molecule and a monodentate nitrate anion occupy the axial positions. The CuCu distances within the dinuclear unit are: 1, 4.022(1); 2, 3.9741(12); 3, 4.0198(7) A. The 4,4′-bpy ligand bridges the dinuclear units to form a ladder type chain, with a CuCu distance measured over the 4,4′-bpy ligand of 11.1220(5) A. The magnetic susceptibility data are interpreted on the basis of the spin Hamiltonian Ĥ=−2J[ŜCu1·Ŝcu2] and yielded 1: J=−47 cm−1, g=2.14; 2: J=−49 cm−1, g=2.04; 3: J=−51 cm−1, g=2.14; 4: J=−51 cm−1, g=2.00; 5: J=−51 cm−1, g=2.07. No interdimer interaction was found for 3. The X-band powder EPR spectra recorded at various temperatures for all compounds are typical of a triplet state, with D values in the range 0.08–0.10 cm−1.


Current Biology | 2010

Transcription-Dependent Cytosine Deamination Is a Novel Mechanism in Ultraviolet Light-Induced Mutagenesis

Giel Hendriks; Fabienne Calléja; Ahmad Besaratinia; Harry Vrieling; Gerd P. Pfeifer; Leon H.F. Mullenders; Jacob G. Jansen; Niels de Wind

Skin cancer is the most ubiquitous cancer type in the Caucasian population, and its incidence is increasing rapidly [1]. Transcribed proliferation-related genes in dermal stem cells are targets for the induction of ultraviolet light (UV)-induced mutations that drive carcinogenesis. We have recently found that transcription of a gene increases its mutability by UV in mammalian stem cells, suggesting a role of transcription in skin carcinogenesis [2]. Here we show that transcription-associated UV-induced nucleotide substitutions are caused by increased deamination of cytosines to uracil within photolesions at the transcribed strand, presumably at sites of stalled transcription complexes. Additionally, via an independent mechanism, transcription of UV-damaged DNA induces the generation of intragenic deletions. We demonstrate that transcription-coupled nucleotide excision repair (TC-NER) provides protection against both classes of transcription-associated mutagenesis. Combined, these results unveil the existence of two mutagenic pathways operating specifically at the transcribed DNA strand of active genes. Moreover, these results uncover a novel role for TC-NER in the suppression of UV-induced genome aberrations and provide a rationale for the efficient induction of apoptosis by stalled transcription complexes.


DNA Repair | 2008

Gene transcription increases DNA damage-induced mutagenesis in mammalian stem cells

Giel Hendriks; Fabienne Calléja; Harry Vrieling; Leon H.F. Mullenders; Jacob G. Jansen; Niels de Wind

DNA damage-induced mutations in actively transcribed genes in stem cells underlie genetic diseases including cancer. Here we investigated whether transcription affects DNA damage-induced gene mutations in mouse embryonic stem cells. To this aim we developed cell lines in which transcription of an Hprt minigene reporter, located at a different genomic positions, is regulated by the tTA2 Tetracycline-controlled transactivator. This allows detection of mutagenic events at both Hprt and tTA2 using a single selection. We found that UV-C and benzo[a]pyrenediolepoxide induced significantly more mutations at the Hprt minigene when the gene was transcribed. The transcription-associated increase in UV-C-induced mutagenesis appears independent of the integration site of the Hprt minigene. Molecular analysis of UV-induced Hprt mutants revealed that transcription of damaged DNA enhances the frequency of nucleotide substitutions and triggers the generation of intragenic deletions at the Hprt minigene. We speculate that these deletions are a result of error-prone DNA end-joining of double strand DNA breaks that are generated when replication forks collide with transcription complexes stalled at DNA lesions.


Mutation Research | 1999

Modulation of the toxic and mutagenic effects induced by methyl methanesulfonate in Chinese hamster ovary cells by overexpression of the rat N-alkylpurine-DNA glycosylase

Fabienne M.G.R. Calléja; Jacob G. Jansen; Harry Vrieling; Françoise Laval; Albert A. van Zeeland

Exposure of mammalian cells to alkylating agents causes transfer of alkyl groups to N- as well as O-atoms of DNA bases. Especially the O-alkylated G and T bases have strong mutagenic properties, since they are capable of mispairing during replication. The mutagenic potential of N-alkylbases is less clear although specific base excision repair (BER) pathways exist which remove those lesions from the DNA. We investigated the relative contribution of N-alkylations to mutation induction at the Hprt gene in cultured Chinese hamster ovary cells (CHO). To this end BER activity in CHO cells was modulated by introduction of an expression vector carrying the rat N-alkylpurine-DNA glycosylase (APDG) gene, which codes for a glycosylase that is able to remove 3-methyladenine and 7-methylguanine from DNA thereby generating apurinic sites. Upon selection of a CHO clone which 10 times overproduced APDG compared to control CHO cells, mutation induction, the mutational spectrum, and cell survival were determined in both cell lines following treatment with methyl methanesulfonate (MMS). The results show that over-expression of APDG renders CHO cells more sensitive for mutation induction as well as cytotoxicity induced by MMS. The involvement of apurinic sites in induction of base pair changes at positions where 3-methyladenine was induced is inferred from the observation that the mutational spectrum of MMS-induced mutations in APDG-CHO cells showed twice as much base pair changes at AT base pairs (33.3%) compared to the spectrum of MMS-induced mutations in CHO-control cells (15.8%).


DNA Repair | 2011

PCNA ubiquitination-independent activation of polymerase η during somatic hypermutation and DNA damage tolerance.

Peter H.L. Krijger; Paul C.M. van den Berk; Niek Wit; Petra Langerak; Jacob G. Jansen; Claude-Agnès Reynaud; Niels de Wind; Heinz Jacobs

The generation of high affinity antibodies in B cells critically depends on translesion synthesis (TLS) polymerases that introduce mutations into immunoglobulin genes during somatic hypermutation (SHM). The majority of mutations at A/T base pairs during SHM require ubiquitination of PCNA at lysine 164 (PCNA-Ub), which activates TLS polymerases. By comparing the mutation spectra in B cells of WT, TLS polymerase η (Polη)-deficient, PCNA(K164R)-mutant, and PCNA(K164R);Polη double-mutant mice, we now find that most PCNA-Ub-independent A/T mutagenesis during SHM is mediated by Polη. In addition, upon exposure to various DNA damaging agents, PCNA(K164R) mutant cells display strongly impaired recruitment of TLS polymerases, reduced daughter strand maturation and hypersensitivity. Interestingly, compared to the single mutants, PCNA(K164R);Polη double-mutant cells are dramatically delayed in S phase progression and far more prone to cell death following UV exposure. Taken together, these data support the existence of PCNA ubiquitination-dependent and -independent activation pathways of Polη during SHM and DNA damage tolerance.


DNA Repair | 2012

Temporally distinct translesion synthesis pathways for ultraviolet light-induced photoproducts in the mammalian genome

Piya Temviriyanukul; Sandrine van Hees-Stuivenberg; Frédéric Delbos; Heinz Jacobs; Niels de Wind; Jacob G. Jansen

Replicative polymerases (Pols) arrest at damaged DNA nucleotides, which induces ubiquitination of the DNA sliding clamp PCNA (PCNA-Ub) and DNA damage signaling. PCNA-Ub is associated with the recruitment or activation of translesion synthesis (TLS) DNA polymerases of the Y family that can bypass the lesions, thereby rescuing replication and preventing replication fork collapse and consequent formation of double-strand DNA breaks. Here, we have used gene-targeted mouse embryonic fibroblasts to perform a comprehensive study of the in vivo roles of PCNA-Ub and of the Y family TLS Pols η, ι, κ, Rev1 and the B family TLS Polζ in TLS and in the suppression of DNA damage signaling and genome instability after exposure to UV light. Our data indicate that TLS Pols ι and κ and the N-terminal BRCT domain of Rev1, that previously was implicated in the regulation of TLS, play minor roles in TLS of DNA photoproducts. PCNA-Ub is critical for an early TLS pathway that replicates both strongly helix-distorting (6-4) pyrimidine-pyrimidone ((6-4)PP) and mildly distorting cyclobutane pyrimidine dimer (CPD) photoproducts. The role of Polη is mainly restricted to early TLS of CPD photoproducts, whereas Rev1 and, in particular, Polζ are essential for the bypass of (6-4)PP photoproducts, both early and late after exposure. Thus, structurally distinct photoproducts at the mammalian genome are bypassed by different TLS Pols in temporally different, PCNA-Ub-dependent and independent fashions.

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Harry Vrieling

Leiden University Medical Center

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Anastasia Tsaalbi-Shtylik

Leiden University Medical Center

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Leon H.F. Mullenders

Leiden University Medical Center

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Heinz Jacobs

Netherlands Cancer Institute

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Anton J.L. de Groot

Leiden University Medical Center

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Piya Temviriyanukul

Leiden University Medical Center

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