Institute of Molecular Cancer Research

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Group Jiricny

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Weller, Shunsuke Kobayashi, Porro, Pizzolato, Saxer, Falke, Keith Caldecott (guest)

Saho Kobayashi, Erb, Jiricny, Giovannini

(not in the photo Kallenberger, Artola )

THE MULTIFACETED MISMATCH REPAIR

During the past two decades, my group has been primarily interested in studying the biochemistry and biology of the postreplicative mismatch repair (MMR) system in human cells. As mutations in MMR genes are associated with hereditary non-polyposis colon cancer (HNPCC, also known as Lynch Syndrome), one of the most common inherited cancer predisposition syndromes, we have been trying to understand how MMR functions and how its malfunction leads to malignant transformation. However, evidence emerging from several different directions implicated MMR proteins also in other pathways of DNA metabolism and we are now changing direction and concentrating our efforts on some of these processes, mostly in human systems. We have also begun to explore the potential of other systems, specifically the DT40 chicken bursal B cells.

We are also revisiting the field of DNA demethylation, with a specific focus on the molecular mechanism of the process and its effects on different pathways of DNA metabolism.

Biochemistry of mismatch repair

To improve replication fidelity, MMR must detect non-Watson-Crick base pairs and direct their repair to the nascent DNA strand. Eukaryotic MMR in vitro requires pre-existing strand discontinuities for initiation; consequently, it has been postulated that MMR in vivo initiates at Okazaki fragment termini in the lagging strand, and at nicks in the leading strand generated by the mismatch-activated MLH1/PMS2 endonuclease. We were able to show that a single ribonucleotide in the vicinity of a mismatch can act as an initiation site for MMR in human cell extracts and that MMR activation in this system is dependent on RNase H2 (Figure 1). As loss of RNase H2 in S. cerevisiae resulted in a mild MMR defect that was reflected in increased mutagenesis, MMR in vivo might also initiate at RNase H2 generated nicks. We therefore proposed that ribonucleotides misincoporated during DNA replication serve as physiological markers of the nascent DNA strand (Ghodgaonkar et al., 2013).

The minimal MMR system could be reconstituted from purified proteins some time ago (Constantin et al., 2005; Zhang et al., 2005), but our genetic screens (Cejka and Jiricny, 2008) and proteomic analysis of the MMR interactome (Cannavo et al., 2007) identified several polypeptides that strongly associate with MLH1 and PMS2, yet are apparently not required for minimal MMR.

In order to learn whether the identified interactors play accessory role(s) in MMR, we set up the reconstituted system in our laboratory, in addition to the in vitro assay that makes use of nuclear extracts of human cells.

We have also set out to study the involvement of nucleases in human MMR. The rationale for this work is the finding that the mutator phenotype of MSH2- and MLH1-deficient cells is considerably stronger than that of cells lacking EXO1, the only exonuclease implicated in MMR to date. This suggests that additional nucleases compensate (at least partially) for the lack of EXO1. One of the candidate nucleases we have been studying is the proofreading activity of polymerase-δ. Using a novel approach developed in our laboratory, we have been able to stably replace the endogenous large subunit of pol-δ with a variant that is error-prone, a variant lacking the 3’→5’ proofreading activity and a third variant affected in both these functions (Figure 2). Phenotypic analysis of these cells revealed that all three cell lines had substantially elevated mutation frequencies, which implies either that their MMR capacity was saturated, or that MMR does not address errors that escape the proofreading exonuclease.

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Figure 1. Schematic representation of ribonucleotide-directed mismatch repair. Ribonucleotides incorporated into the nascent strand during replication are removed by RNasH2. Should a mismatch be generated in the vicinity, the MMR system can hijack the strand break arising during the ribonucleotide removal as an initiation site for EXO1-catalysed degradation of the error-containing nascent strand. The single-stranded gasp is stabilised by RPA, until it is filled-in by the replicative polymerase.

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Figure 2. Biochemical characterization of polymerase-δ variants expressed in human cells. The enzymes were isolated by affinity chromatography and tested for their ability to extend a radiolabelled 17-mer primer annealed to a 31-mer template. All enzyme variants, wild type (WT), error-prone (EP), proofreading-deficient (PD) or the double mutant (DM) could extend the primer in the presence of all four dNTPs, albeit with varying efficiencies. The exonuclease defect in the PD and DM variants is clearly evident from the lack of degradation products of the 17-mer. All variants were able to incorporate dCMP (but no other nucleotide) opposite the G at position 18 of the template. The figure represents an autoradiograph of a 10% polyacrylamide gel.

MMR and interstrand cross-link repair

In 2007, we identified KIAA1018 as a strong interactor of the MMR protein MLH1. Because the protein is recruited to chromatin by mono-ubiquitylated Fanconi protein FANCD2, it has been renamed FANCD2-associated nuclease 1, FAN1. We could show that FAN1 is an exo/endonuclease, which preferentially cleaves 5’ flaps and D-loops in vitro. We were able to show that human (Kratz et al., 2010) and chicken DT40 (Yoshikiyo et al., 2010) cells lacking FAN1 were hypersensitive to agents that induce interstrand cross-links (ICLs), and that FAN1 deficiency also lowered recombination efficiency and double-strand break repair. Interestingly, although hypersensitivity to ICL-inducing agents is one of the key hallmarks of Fanconi anemia (FA), the FAN1 gene does not appear to be mutated in FA patients. We are now trying to understand the biological relevance and/or importance of the binding of FAN1 to MLH1 and PMS2, as well as identify its molecular role in the processing of ICLs.

The role of MMR proteins in antibody diversification

 The generation of our vast antibody repertoire involves three processes: VDJ recombination, somatic hypermutation (SHM) and class switch recombination (CSR). All of these processes irreversibly alter the genome of B cells. Whereas the random recombination of the variable (V), diversity (D) and join (J) regions of the immunoglobulin (Ig) genes takes place in unstimulated B-cells already in the bone marrow, the latter processes are initiated upon antigen stimulation of the cells in germinal centers. SHM/CSR is triggered by activation-induced cytidine deaminase (AID), which is induced in antigen-stimulated B cells and which converts cytosines in certain sequence contexts to uracils. Although uracil processing by base excision repair is generally error-free, in stimulated B cells it gives rise to mutations. Surprisingly, evidence obtained from knock out mouse models and, more recently, also from patients, showed that a subset of these mutations is dependent on MMR. Thus, while MMR is a high-fidelity process, MMR proteins appear to act as mutators during SHM/CSR. Using defined uracil-containing substrates, we could show that base excision repair and MMR compete for the AID-generated U/G mispairs. This interference gives rise to long tracts of single-stranded DNA, which are not efficiently filled-in by the replicative polymerases due to low enzyme concentrations and depleted nucleotide pools outside of S phase. This appears to trigger mono-ubiquitylation of PCNA and recruitment to DNA of translesion polymerases such as polymerase-η. We postulate that the deployment of these error-prone polymerases in the repair of MMR-generated gaps leads to mutations during SHM/CSR (Figure 3).

We are currently attempting to obtain mechanistic insights into the CSR process, using an in vitro system capable of mimicking the AID-triggered in vivo recombination events.

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Figure 3. Putative scheme of MMR function during G1- and S-phases of the cell cycle. Lesions bound by MMR proteins outside of S-phase activate non-canonical MMR, during which the endonuclease activity of MutLα introduces nicks into either DNA strand. These might be used for loading of EXO1, which would result in the generation of long single-stranded gaps. Due to low nucleotide pool concentrations and low levels of replicative polymerases, the gaps might persist for some time, which could trigger PCNA ubiquitylation and recruitment of error-prone polymerase(s) such as pol-η. In contrast, lesions generated during S-phase would be repaired with high fidelity, due to the existence of free termini that direct MMR to the nascent strand, the ready availability of dNTPs and higher concentrations of replicative polymerases.

Repair of O6-methylguanine in Xenopus laevis egg extracts

The MMR system has been shown to be involved in the processing of DNA damage other than base/base mismatches and IDLs. It is largely responsible for the cytotoxicity of the mutgenic O6-methylguanine (MeG), such that MMR-deficient cells are up to 100-fold more resistant to killing by methylating agents of the SN1 type than their MMR-proficient counterparts. In order to understand the molecular basis of this resistance, we asked whether DNA substrates carrying defined base modifications are addressed by the MMR system in vitro. We devised a method of preparing such substrates, using a combination of primer extension reactions on single-stranded substrates and a “nickase” – an enzyme capable of incising specifically only a single DNA strand of its recognition sequence. We succeeded in incorporating MeG into our substrates, and were able to show that it is addressed by the MMR system. However, our in vitro MMR assay does not faithfully mirror the process in which a mispair is addressed immediately after it was generated by the polymerase, i.e. in the context of DNA replication. In order to gain insights into the mechanism of postreplicative MMR, we are attempting to make use of MeG present in the template that is undergoing replication in nucleoplasmic extracts of Xenopus laevis eggs. In this system, we can follow replication, repair, DNA damage signalling and possibly also recombination in the same assay.

Publications

Bregenhorn, Stephanie; Kallenberger, Lia; Artola-Borán, Mariela; Peña-Diaz, Javier; Jiricny, Josef (2016). Non-canonical uracil processing in DNA gives rise to double-strand breaks and deletions: relevance to class switch recombination. Nucleic Acids Research, 44(6):2691-2705.

Pizzolato, Julia; Mukherjee, Shivam; Schaerer, Orlando D; Jiricny, Josef (2015). FANCD2-associated nuclease 1, but not exonuclease 1 or flap endonuclease 1, is able to unhook DNA interstrand cross-links in vitro. Journal of Biological Chemistry:1-20.

Repmann, Simone; Olivera-Harris, Maite; Jiricny, Josef (2015). Influence of Oxidized Purine Processing on Strand Directionality of Mismatch Repair. Journal of Biological Chemistry, 290(16):9986-9999.

Olivera Harris, Maite; Kallenberger, Lia; Artola Borán, Mariela; Enoiu, Milica; Costanzo, Vincenzo; Jiricny, Josef (2015). Mismatch repair-dependent metabolism of O(6)-methylguanine-containing DNA in Xenopus laevis egg extracts. DNA repair, 28C:1-7.

Gentili, Christian; Castor, Dennis; Kaden, Svenja; Lauterbach, David; Gysi, Mario; Steigemann, Patrick; Gerlich, Daniel W; Jiricny, Josef; Ferrari, Stefano (2015). Chromosome Missegregation Associated with RUVBL1 Deficiency. PLoS ONE, 10(7):e0133576.

Vonlanthen, Janine; Okoniewski, Michal J; Menigatti, Mirco; Cattaneo, Elisa; Pellegrini-Ochsner, Daniela; Haider, Ritva; Jiricny, Josef; Staiano, Teresa; Buffoli, Federico; Marra, Giancarlo (2014). A comprehensive look at transcription factor gene expression changes in colorectal adenomas. BMC Cancer, 14(1):46.

Bregenhorn, Stephanie; Jiricny, Josef (2014). Biochemical characterization of a cancer-associated E109K missense variant of human exonuclease 1. Nucleic Acids Research, 42(11):7096-7103.

Alvino, Ester; Passarelli, Francesca; Cannavò, Elda; Fortes, Cristina; Mastroeni, Simona; Caporali, Simona; Jiricny, Josef; Cappellini, Gian Carlo Antonini; Scoppola, Alessandro; Marchetti, Paolo; Modesti, Andrea; D'Atri, Stefania (2014). High expression of the mismatch repair protein MSH6 is associated with poor patient survival in melanoma. American Journal of Clinical Pathology, 142(1):121-132.

Ghodgaonkar, Medini Manohar; Kehl, Patrick; Ventura, Ilenia; Hu, Liyan; Bignami, Margherita; Jiricny, Josef (2014). Phenotypic characterization of missense polymerase-δ mutations using an inducible protein-replacement system. Nature Communications, 5:4990.

Tiwari, Amit; Schneider, Mirjam; Fiorino, Antonio; Haider, Ritva; Okoniewski, Michal J; Roschitzki, Bernd; Uzozie, Anuli; Menigatti, Mirco; Jiricny, Josef; Marra, Giancarlo (2013). Early insights into the function of KIAA1199, a markedly overexpressed protein in human colorectal tumors. PLoS ONE, 8(7):e69473.

Menigatti, M; Staiano, T; Manser, C N; Bauerfeind, P; Komljenovic, A; Robinson, M; Jiricny, J; Buffoli, F; Marra, G (2013). Epigenetic silencing of monoallelically methylated miRNA loci in precancerous colorectal lesions. Oncogenesis, 2:e56.

Campo, Vanina A; Patenaude, Anne-Marie; Kaden, Svenja; Horb, Lori; Firka, Daniel; Jiricny, Josef; Di Noia, Javier M (2013). MSH6- or PMS2-deficiency causes re-replication in DT40 B cells, but it has little effect on immunoglobulin gene conversion or on repair of AID-generated uracils. Nucleic Acids Research, 41(5):3032-3046.

Jiricny, Josef (2013). Postreplicative mismatch repair. Cold Spring Harbor Perspectives in Biology, 5(4):online.

Ghodgaonkar, Medini Manohar; Lazzaro, Federico; Olivera-Pimentel, Maite; Artola-Borán, Mariela; Cejka, Petr; Reijns, Martin A; Jackson, Andrew P; Plevani, Paolo; Muzi-Falconi, Marco; Jiricny, Josef (2013). Ribonucleotides misincorporated into DNA act as strand-discrimination signals in eukaryotic mismatch repair. Molecular Cell, 50(3):323-332.

Dittrich, Christina M; Kratz, Katja; Sendoel, Ataman; Gruenbaum, Yosef; Jiricny, Josef; Hengartner, Michael O (2012). LEM-3 - A LEM domain containing nuclease involved in the DNA damage response in C. elegans. PLoS ONE, 7(2):e24555.

Schöpf, B; Bregenhorn, S; Quivy, J P; Kadyrov, F A; Almouzni, G; Jiricny, J (2012). Interplay between mismatch repair and chromatin assembly. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 109(6):1895-1900.

Peña-Diaz, Javier; Jiricny, Josef (2012). Mammalian mismatch repair: error-free or error-prone? Trends in Biochemical Sciences, 37(5):206-214.

Peña-Diaz, Javier; Bregenhorn, Stephanie; Ghodgaonkar, Medini; Follonier, Cindy; Artola-Borán, Mariela; Castor, Dennis; Lopes, Massimo; Sartori, Alessandro A; Jiricny, Josef (2012). Noncanonical Mismatch Repair as a Source of Genomic Instability in Human Cells. Molecular Cell, 47(5):669-680.

Enoiu, Milica; Jiricny, Josef; Schärer, Orlando D (2012). Repair of cisplatin-induced DNA interstrand crosslinks by a replication-independent pathway involving transcription-coupled repair and translesion synthesis. Nucleic Acids Research, 40(18):8953-8964.

Brachner, Andreas; Braun, Juliane; Ghodgaonkar, Medini; Castor, Dennis; Zlopasa, Livija; Ehrlich, Veronika; Jiricny, Josef; Gotzmann, Josef; Knasmüller, Siegfried; Foisner, Roland (2012). The endonuclease Ankle1 requires its LEM and GIY-YIG motifs for DNA cleavage in vivo. Journal of Cell Science, 125(Pt 4):1048-1057.

Vasovcak, P; Krepelova, A; Menigatti, M; Puchmajerova, A; Skapa, P; Augustinakova, A; Amann, G; Wernstedt, A; Jiricny, J; Marra, G; Wimmer, K (2012). Unique mutational profile associated with a loss of TDG expression in the rectal cancer of a patient with a constitutional PMS2 deficiency. DNA Repair, 11(7):616-623.

Veljkovic, E; Jiricny, J; Menigatti, M; Rehrauer, H; Han, W (2011). Chronic exposure to cigarette smoke condensate in vitro induces epithelial to mesenchymal transition-like changes in human bronchial epithelial cells, BEAS-2B. Toxicology in Vitro, 25(2):446-453.

Cortázar, D; Kunz, C; Selfridge, J; Lettieri, T; Saito, Y; Macdougall, E; Wirz, A; Schuermann, D; Jacobs, A L; Siegrist, F; Steinacher, R; Jiricny, J; Bird, A; Schär, P (2011). Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability. Nature, 470(7334):419-423.

Kovac, M; Laczko, E; Haider, R; Jiricny, J; Mueller, H; Heinimann, K; Marra, G (2011). Familial colorectal cancer: eleven years of data from a registry program in Switzerland. Familial Cancer, 10(3):605-616.

Yamamoto, K N; Kobayashi, S; Tsuda, M; Kurumizaka, H; Takata, M; Kono, K; Jiricny, J; Takeda, S; Hirota, K (2011). Involvement of SLX4 in interstrand cross-link repair is regulated by the Fanconi anemia pathway. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 108(16):6492-6496.

Cattaneo, E; Laczko, E; Buffoli, F; Zorzi, F; Bianco, M A; Menigatti, M; Bartosova, Z; Haider, R; Helmchen, B; Sabates-Bellver, J; Tiwari, A; Jiricny, J; Marra, G (2011). Preinvasive colorectal lesion transcriptomes correlate with endoscopic morphology (polypoid vs. nonpolypoid). EMBO Molecular Medicine, 3(6):334-347.

Jiricny, J (2010). DNA repair: how MutM finds the needle in a haystack. Current Biology, 20(4):R145-R147.

Kratz, K; Schöpf, B; Kaden, S; Sendoel, A; Eberhard, R; Lademann, C; Cannavó, E; Sartori, A A; Hengartner, M O; Jiricny, J (2010). Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to interstrand crosslinking agents. Cell, 142(1):77-88.

Yoshikiyo, K; Kratz, K; Hirota, K; Nishihara, K; Takata, M; Kurumizaka, H; Horimoto, S; Takeda, S; Jiricny, J (2010). KIAA1018/FAN1 nuclease protects cells against genomic instability induced by interstrand cross-linking agents. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 107(50):21553-21557.

Peña-Diaz, J; Jiricny, J (2010). PCNA and MutLα: partners in crime in triplet repeat expansion? Proceedings of the National Academy of Sciences of the United States of America (PNAS), 107(38):16409-16410.

Schanz, S; Castor, D; Fischer, F; Jiricny, J (2009). Interference of mismatch and base excision repair during the processing of adjacent U/G mispairs may play a key role in somatic hypermutation. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 106(14):5593-5598.

Güthlein, C; Wanner, R M; Sander, P; Davis, E O; Bosshard, M; Jiricny, J; Böttger, E C; Springer, B (2009). Characterisation of the mycobacterial NER system reveals novel functions of uvrD1 helicase. Journal of Bacteriology, 191(2):555-562.

Menigatti, M; Cattaneo, E; Sabates-Bellver, J; Ilinsky, V V; Went, P; Buffoli, F; Marquez, V E; Jiricny, J; Marra, G (2009). The protein tyrosine phosphatase receptor type R gene is an early and frequent target of silencing in human colorectal tumorigenesis. Molecular Cancer Therapeutics, 8:124.

Wanner, R M; Castor, D; Güthlein, C; Böttger, E C; Springer, B; Jiricny, J (2009). The uracil DNA glycosylase UdgB of Mycobacterium smegmatis protects the organism from the mutagenic effects of cytosine and adenine deamination. Journal of Bacteriology, 191(20):6312-6319.

Cejka, P; Jiricny, J (2008). Interplay of DNA repair pathways controls methylation damage toxicity in Saccharomyces cerevisiae. Genetics, 179(4):1835-1844.

Jiricny, J; Menigatti, M (2008). DNA Cytosine demethylation: are we getting close? Cell, 135(7):1167-1169.

Ollila, S; Dermadi Bebek, D; Jiricny, J; Nyström, M (2008). Mechanisms of pathogenicity in human MSH2 missense mutants. Human Mutation, 29(11):1355-63.

Bujalkova, M; Zavodna, K; Krivulcik, T; Ilencikova, D; Wolf, B; Kovac, M; Karner-Hanusch, J; Heinimann, K; Marra, G; Jiricny, J; Bartosova, Z (2008). Multiplex SNaPshot genotyping for detecting loss of heterozygosity in the mismatch-repair genes MLH1 and MSH2 in microsatellite-unstable tumors. Clinical Chemistry, 54:1844-1854.

Sammalkorpi, H; Alhopuro, P; Lehtonen, R; Tuimala, J; Mecklin, J-P; Järvinen, H J; Jiricny, J; Karhu, A; Aaltonen, L A (2007). Background mutation frequency in microsatellite-unstable colorectal cancer. Cancer Research, 67(12):5691-5698.

Cannavo, E; Gerrits, B; Marra, G; Schlapbach, R; Jiricny, J (2007). Characterization of the interactome of the human MutL homologues MLH1, PMS1, and PMS. Journal of Biological Chemistry, 282(5):2976-86.

Pani, E; Stojic, L; El-Shemerly, M; Jiricny, J; Ferrari, S (2007). Mismatch repair status and the response of human cells to cisplatin. Cell Cycle, 6(14):1796-1802.

Mojas, N; Lopes, M; Jiricny, J (2007). Mismatch repair-dependent processing of methylation damage gives rise to persistent single-stranded gaps in newly replicated DNA. Genes and Development, 21(24):3342-55.

Sabates-Bellver, J; Van der Flier, L G; de Palo, M; Cattaneo, E; Maake, C; Rehrauer, H; Laczko, E; Kurowski, M A; Bujnicki, J M; Menigatti, M; Luz, J; Ranalli, T V; Gomes, V; Pastorelli, A; Faggiani, R; Anti, M; Jiricny, J; Clevers, H; Marra, G (2007). Transcriptome profile of human colorectal adenomas. Molecular Cancer Research, 5(12):1263-1275.

Alvino, E; Castiglia, D; Caporali, S; Pepponi, R; Caporaso, P; Lacal, P M; Marra, G; Fischer, F; Zambruno, G; Bonmassar, E; Jiricny, J; D'Atri, S (2006). A single cycle of treatment with temozolomide, alone or combined with O(6)-benzylguanine, induces strong chemoresistance in melanoma cell clones in vitro: role of O(6)-methylguanine-DNA methyltransferase and the mismatch repair system. International Journal of Oncology, 29(4):785-797.

Baerenfaller, K; Fischer, F; Jiricny, J (2006). Characterization of the "mismatch repairosome" and its role in the processing of modified nucleosides in vitro. Methods in Enzymology, 408:285-303.

Jiricny, J (2006). MutLalpha: at the cutting edge of mismatch repair. Cell, 126(2):239-241.

Zavodna, K; Bujalkova, M; Krivulcik, T; Alemayehu, A; Skorvaga, M; Marra, G; Fridrichova, I; Jiricny, J; Bartosova, Z (2006). Novel and recurrent germline alterations in the MLH1 and MSH2 genes identified in hereditary nonpolyposis colorectal cancer patients in Slovakia. Neoplasma, 53(4):269-276.

Jiricny, J (2006). The multifaceted mismatch-repair system. Nature Reviews. Molecular Cell Biology, 7(5):335-346.

Lingaraju, G M; Sartori, A A; Kostrewa, D; Prota, A E; Jiricny, J; Winkler, F K (2005). A DNA glycosylase from Pyrobaculum aerophilum with an 8-oxoguanine binding mode and a noncanonical helix-hairpin-helix structure. Structure, 13(1):87-98.

Szadkowski, M; Iaccarino, I; Heinimann, K; Marra, G; Jiricny, J (2005). Characterization of the mismatch repair defect in the human lymphoblastoid MT1 cells. Cancer Research, 65(11):4525-4529.

Marra, G; Jiricny, J (2005). DNA mismatch repair and colon cancer. In: Nigg, E A. Genome Instability in Cancer Development. Netherland: Springer, 85-123.

di Pietro, M; Sabates-Bellver, J; Menigatti, M; Bannwart, F; Schnider, A; Russell, A; Truninger, K; Jiricny, J; Marra, G (2005). Defective DNA mismatch repair determines a characteristic transcriptional profile in proximal colon cancers. Gastroenterology, 129(3):1047-1059.

El-Shemerly, M; Janscak, P; Hess, D; Jiricny, J; Ferrari, S (2005). Degradation of human exonuclease 1b upon DNA synthesis inhibition. Cancer Research, 65(9):3604-3609.

Cannavo, E; Marra, G; Sabates-Bellver, J; Menigatti, M; Lipkin, S M; Fischer, F; Cejka, P; Jiricny, J (2005). Expression of the MutL homologue hMLH3 in human cells and its role in DNA mismatch repair. Cancer Research, 65(23):10759-10766.

Stojic, L; Cejka, P; Jiricny, J (2005). High doses of SN1 type methylating agents activate DNA damage signaling cascades that are largely independent of mismatch repair. Cell Cycle, 4(3):473-477.

Cejka, P; Mojas, N; Gillet, L; Schär, P; Jiricny, J (2005). Homologous recombination rescues mismatch-repair-dependent cytotoxicity of S(N)1-type methylating agents in S. cerevisiae. Current Biology, 15(15):1395-1400.

Truninger, K; Menigatti, M; Luz, J; Russell, A; Haider, R; Gebbers, J-O; Bannwart, F; Yurtsever, H; Neuweiler, J; Riehle, H-M; Cattaruzza, M S; Heinimann, K; Schär, P; Jiricny, J; Marra, G (2005). Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Gastroenterology, 128(5):1160-1171.

Chastel, C; Jiricny, J; Jaussi, R (2004). Activation of stress-responsive promoters by ionizing radiation for deployment in targeted gene therapy. DNA Repair, 3(3):201-215.

Caporali, S; Falcinelli, S; Starace, G; Russo, M T; Bonmassar, E; Jiricny, J; D'Atri, S (2004). DNA damage induced by temozolomide signals to both ATM and ATR: role of the mismatch repair system. Molecular Pharmacology, 66(3):478-491.

Papouli, E; Cejka, P; Jiricny, J (2004). Dependence of the cytotoxicity of DNA-damaging agents on the mismatch repair status of human cells. Cancer Research, 64(10):3391-3394.

Garcia, P L; Liu, Y; Jiricny, J; West, S C; Janscak, P (2004). Human RECQ5beta, a protein with DNA helicase and strand-annealing activities in a single polypeptide. EMBO Journal, 23(14):2882-2891.

Cejka, P; Stojic, L; Marra, G; Jiricny, J (2004). Is mismatch repair really required for ionizing radiation-induced DNA damage signaling? Nature Genetics, 36(5):432-3; author reply 434.

Stojic, L; Brun, R; Jiricny, J (2004). Mismatch repair and DNA damage signalling. DNA Repair, 3(8-9):1091-1101.

Stojic, L; Mojas, N; Cejka, P; Di Pietro, M; Ferrari, S; Marra, G; Jiricny, J (2004). Mismatch repair-dependent G2 checkpoint induced by low doses of SN1 type methylating agents requires the ATR kinase. Genes and Development, 18(11):1331-1344.

Sartori, A A; Lingaraju, G M; Hunziker, P; Winkler, F K; Jiricny, J (2004). Pa-AGOG, the founding member of a new family of archaeal 8-oxoguanine DNA-glycosylases. Nucleic Acids Research, 32(22):6531-6539.

Jiricny, J (2004). Unfaithful DNA polymerase caught in the act. Molecular Cell, 13(6):768-769.

Castiglia, D; Pagani, E; Alvino, E; Vernole, P; Marra, G; Cannavò, E; Jiricny, J; Zambruno, G; D'Atri, S (2003). Biallelic somatic inactivation of the mismatch repair gene MLH1 in a primary skin melanoma. Genes, Chromosomes & Cancer, 37(2):165-175.

Jiricny, J; Marra, G (2003). DNA repair defects in colon cancer. Current Opinion in Genetics & Development, 13(1):61-69.

Cejka, P; Marra, G; Hemmerle, C; Cannavó, E; Storchova, Z; Jiricny, J (2003). Differential killing of mismatch repair-deficient and -proficient cells: towards the therapy of tumors with microsatellite instability. Cancer Research, 63(23):8113-8117.

Sartori, A A; Jiricny, J (2003). Enzymology of base excision repair in the hyperthermophilic archaeon Pyrobaculum aerophilum. Journal of Biological Chemistry, 278(27):24563-24576.

Cejka, P; Stojic, L; Mojas, N; Russell, A F; Heinimann, K; Cannavó, E; di Pietro, M; Marra, G; Jiricny, J (2003). Methylation-induced G(2)/M arrest requires a full complement of the mismatch repair protein hMLH1. EMBO Journal, 22(9):2245-2254.

di Pietro, M; Marra, G; Cejka, P; Stojic, L; Menigatti, M; Cattaruzza, M S; Jiricny, J (2003). Mismatch repair-dependent transcriptome changes in human cells treated with the methylating agent N-methyl-n'-nitro-N-nitrosoguanidine. Cancer Research, 63(23):8158-8166.

Marra, G; Jiricny, J (2003). Multiple colorectal adenomas--is their number up? New England Journal of Medicine, 348(9):845-847.

Bartosova, Z; Fridrichova, I; Bujalkova, M; Wolf, B; Ilencikova, D; Krizan, P; Hlavcak, P; Palaj, J; Lukac, L; Lukacova, M; Böör, A; Haider, R; Jiricny, J; Nyström-Lahti, M; Marra, G (2003). Novel MLH1 and MSH2 germline mutations in the first HNPCC families identified in Slovakia. Human Mutation, 21(4):449.

Pedrazzi, G; Bachrati, C Z; Selak, N; Studer, I; Petkovic, M; Hickson, I D; Jiricny, J; Stagljar, I (2003). The Bloom's syndrome helicase interacts directly with the human DNA mismatch repair protein hMSH6. Biological Chemistry, 384(8):1155-1164.

Pepponi, R; Marra, G; Fuggetta, M P; Falcinelli, S; Pagani, E; Bonmassar, E; Jiricny, J; D'Atri, S (2003). The effect of O6-alkylguanine-DNA alkyltransferase and mismatch repair activities on the sensitivity of human melanoma cells to temozolomide, 1,3-bis(2-chloroethyl)1-nitrosourea, and cisplatin. Journal of Pharmacology and Experimental Therapeutics, 304(2):661-668.

Hardeland, U; Bentele, M; Jiricny, J; Schär, P (2003). The versatile thymine DNA-glycosylase: a comparative characterization of the human, Drosophila and fission yeast orthologs. Nucleic Acids Research, 31(9):2261-2271.

Sartori, A A; Fitz-Gibbon, S; Yang, H; Miller, J H; Jiricny, J (2002). A novel uracil-DNA glycosylase with broad substrate specificity and an unusual active site. EMBO Journal, 21(12):3182-3191.

Hinks, J A; Evans, M C W; De Miguel, Y; Sartori, A A; Jiricny, J; Pearl, L H (2002). An iron-sulfur cluster in the family 4 uracil-DNA glycosylases. Journal of Biological Chemistry, 277(19):16936-19640.

Jiricny, J (2002). DNA repair: An APE that proofreads. Nature, 415(6872):593-594.

Jiricny, J (2002). DNA repair: bioinformatics helps reverse methylation damage. Current Biology, 12(24):R846-R848.

Yang, H; Chiang, J-H; Fitz-Gibbon, S; Lebel, M; Sartori, A A; Jiricny, J; Slupska, M M; Miller, J H (2002). Direct interaction between uracil-DNA glycosylase and a proliferating cell nuclear antigen homolog in the crenarchaeon Pyrobaculum aerophilum. Journal of Biological Chemistry, 277(25):22271-22278.

Kuismanen, S A; Moisio, A-L; Schweizer, P; Truninger, K; Salovaara, R; Arola, J; Butzow, R; Jiricny, J; Nyström-Lahti, M; Peltomäki, P (2002). Endometrial and colorectal tumors from patients with hereditary nonpolyposis colon cancer display different patterns of microsatellite instability. American Journal of Pathology, 160(6):1953-1958.

Nyström-Lahti, M; Perrera, C; Räschle, M; Panyushkina-Seiler, E; Marra, G; Curci, A; Quaresima, B; Costanzo, F; D'Urso, M; Venuta, S; Jiricny, J (2002). Functional analysis of MLH1 mutations linked to hereditary nonpolyposis colon cancer. Genes, Chromosomes & Cancer, 33(2):160-167.

Trojan, J; Zeuzem, S; Randolph, A; Hemmerle, C; Brieger, A; Raedle, J; Plotz, G; Jiricny, J; Marra, G (2002). Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system. Gastroenterology, 122(1):211-219.

Alvino, E; Marra, G; Pagani, E; Falcinelli, S; Pepponi, R; Perrera, C; Haider, R; Castiglia, D; Ferranti, G; Bonmassar, E; Jiricny, J; Zambruno, G; D'Atri, S (2002). High-frequency microsatellite instability is associated with defective DNA mismatch repair in human melanoma. Journal of Investigative Dermatology, 118(1):79-86.

Szadkowski, M; Jiricny, J (2002). Identification and functional characterization of the promoter region of the human MSH6 gene. Genes, Chromosomes & Cancer, 33(1):36-46.

Hardeland, U; Steinacher, R; Jiricny, J; Schär, P (2002). Modification of the human thymine-DNA glycosylase by ubiquitin-like proteins facilitates enzymatic turnover. EMBO Journal, 21(6):1456-1464.

Räschle, M; Dufner, P; Marra, G; Jiricny, J (2002). Mutations within the hMLH1 and hPMS2 subunits of the human MutLalpha mismatch repair factor affect its ATPase activity, but not its ability to interact with hMutSalpha. Journal of Biological Chemistry, 277(24):21810-21820.

Sartori, A A; Schär, P; Fitz-Gibbon, S; Miller, J H; Jiricny, J (2001). Biochemical characterization of uracil processing activities in the hyperthermophilic archaeon Pyrobaculum aerophilum. Journal of Biological Chemistry, 276(32):29979-29986.

Pedrazzi, G; Perrera, C; Blaser, H; Kuster, P; Marra, G; Davies, S L; Ryu, G H; Freire, R; Hickson, I D; Jiricny, J; Stagljar, I (2001). Direct association of Bloom's syndrome gene product with the human mismatch repair protein MLH1. Nucleic Acids Research, 29(21):4378-4386.

Schweizer, P; Moisio, A L; Kuismanen, S A; Truninger, K; Vierumäki, R; Salovaara, R; Arola, J; Butzow, R; Jiricny, J; Peltomäki, P; Nyström-Lahti, M (2001). Lack of MSH2 and MSH6 characterizes endometrial but not colon carcinomas in hereditary nonpolyposis colorectal cancer. Cancer Research, 61(7):2813-2815.

Marra, G; D'Atri, S; Yan, H; Perrera, C; Cannavo', E; Vogelstein, B; Jiricny, J (2001). Phenotypic analysis of hMSH2 mutations in mouse cells carrying human chromosomes. Cancer Research, 61(21):7719-7721.

Schärer, O D; Jiricny, J (2001). Recent progress in the biology, chemistry and structural biology of DNA glycosylases. BioEssays, 23(3):270-281.

Hardeland, U; Bentele, M; Lettieri, T; Steinacher, R; Jiricny, J; Schär, P (2001). Thymine DNA glycosylase. In: Moldave, K; Mitra, S; McCullough, A K; Lloyd, R S; Wilson, S H. Base Excision Repair. New York: Elsevier, 235-253.

Marra, G; D'Atri, S; Corti, C; Bonmassar, L; Cattaruzza, M S; Schweizer, P; Heinimann, K; Bartosova, Z; Nyström-Lahti, M; Jiricny, J (2001). Tolerance of human MSH2+/- lymphoblastoid cells to the methylating agent temozolomide. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 98(13):7164-7169.

Kleczkowska, H E; Marra, G; Lettieri, T; Jiricny, J (2001). hMSH3 and hMSH6 interact with PCNA and colocalize with it to replication foci. Genes and Development, 15(6):724-736.

Pepponi, R; Graziani, G; Falcinelli, S; Vernole, P; Levati, L; Lacal, P M; Pagani, E; Bonmassar, E; Jiricny, J; D'Atri, S (2001). hMSH3 overexpression and cellular response to cytotoxic anticancer agents. Carcinogenesis, 22(8):1131-1137.

Jiricny, J (2000). Mismatch repair: the praying hands of fidelity. Current Biology, 10(21):R788-R790.

Yan, H; Papadopoulos, N; Marra, G; Perrera, C; Jiricny, J; Boland, C R; Lynch, H T; Chadwick, R B; de la Chapelle, A; Berg, K; Eshleman, J R; Yuan, W; Markowitz, S; Laken, S J; Lengauer, C; Kinzler, K W; Vogelstein, B (2000). Conversion of diploidy to haploidy. Nature, 403(6771):723-724.

Ichikawa, M; Nakane, H; Marra, G; Corti, C; Jiricny, J; Fitch, M; Ford, J M; Ikejima, M; Shimada, T; Yoshino, M; Takeuchi, S; Nakatsu, Y; Tanaka, K (2000). Decreased UV sensitivity, mismatch repair activity and abnormal cell cycle checkpoints in skin cancer cell lines derived from UVB-irradiated XPA-deficient mice. Mutation Research, 459(4):285-298.

Bearzatto, A; Szadkowski, M; Macpherson, P; Jiricny, J; Karran, P (2000). Epigenetic regulation of the MGMT and hMSH6 DNA repair genes in cells resistant to methylating agents. Cancer Research, 60(12):3262-3270.

Jiricny, J (2000). Mediating mismatch repair. Nature Genetics, 24(1):6-8.

Dufner, P; Marra, G; Räschle, M; Jiricny, J (2000). Mismatch recognition and DNA-dependent stimulation of the ATPase activity of hMutSalpha is abolished by a single mutation in the hMSH6 subunit. Journal of Biological Chemistry, 275(47):36550-36555.

Jiricny, J; Nyström-Lahti, M (2000). Mismatch repair defects in cancer. Current Opinion in Genetics & Development, 10(2):157-161.

Zhang, H; Marra, G; Jiricny, J; Maher, V M; McCormick, J J (2000). Mismatch repair is required for O(6)-methylguanine-induced homologous recombination in human fibroblasts. Carcinogenesis, 21(9):1639-1646.

Iaccarino, I; Marra, G; Dufner, P; Jiricny, J (2000). Mutation in the magnesium binding site of hMSH6 disables the hMutSalpha sliding clamp from translocating along DNA. Journal of Biological Chemistry, 275(3):2080-2086.

Hardeland, U; Bentele, M; Jiricny, J; Schär, P (2000). Separating substrate recognition from base hydrolysis in human thymine DNA glycosylase by mutational analysis. Journal of Biological Chemistry, 275(43):33449-33456.

Barrett, T E; Schärer, O D; Savva, R; Brown, T; Jiricny, J; Verdine, G L; Pearl, L H (1999). Crystal structure of a thwarted mismatch glycosylase DNA repair complex. EMBO Journal, 18(23):6599-6609.

Räschle, M; Marra, G; Nyström-Lahti, M; Schär, P; Jiricny, J (1999). Identification of hMutLbeta, a heterodimer of hMLH1 and hPMS1. Journal of Biological Chemistry, 274(45):32368-32375.

Hendrich, B; Hardeland, U; Ng, H H; Jiricny, J; Bird, A (1999). The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites. Nature, 401(6750):301-304.

Barrett, T E; Savva, R; Panayotou, G; Barlow, T; Brown, T; Jiricny, J; Pearl, L H (1998). Crystal structure of a G:T/U mismatch-specific DNA glycosylase: mismatch recognition by complementary-strand interactions. Cell, 92(1):117-129.

Marra, G; Iaccarino, I; Lettieri, T; Roscilli, G; Delmastro, P; Jiricny, J (1998). Mismatch repair deficiency associated with overexpression of the MSH3 gene. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 95(15):8568-8573.

Jiricny, J (1998). Replication errors: cha(lle)nging the genome. EMBO Journal, 17(22):6427-6436.

Iaccarino, I; Marra, G; Palombo, F; Jiricny, J (1998). hMSH2 and hMSH6 play distinct roles in mismatch binding and contribute differently to the ATPase activity of hMutSalpha. EMBO Journal, 17(9):2677-2686.

Gallinari, P; Jiricny, J (1996). A new class of uracil-DNA glycosylases related to human thymine-DNA glycosylase. Nature, 383(6602):735-738.

Neddermann, P; Gallinari, P; Lettieri, T; Schmid, D; Truong, O; Hsuan, J J; Wiebauer, K; Jiricny, J (1996). Cloning and expression of human G/T mismatch-specific thymine-DNA glycosylase. Journal of Biological Chemistry, 271(22):12767-12774.

Palombo, F; Iaccarino, I; Nakajima, E; Ikejima, M; Shimada, T; Jiricny, J (1996). hMutSbeta, a heterodimer of hMSH2 and hMSH3, binds to insertion/deletion loops in DNA. Current Biology, 6(9):1181-1184.

Palombo, F; Gallinari, P; Iaccarino, I; Lettieri, T; Hughes, M; D'Arrigo, A; Truong, O; Hsuan, J J; Jiricny, J (1995). GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells. Science, 268(5219):1912-1914.

Wiebauer, K; Jiricny, J (1989). In vitro correction of G.T mispairs to G.C pairs in nuclear extracts from human cells. Nature, 339(6221):234-236.

Brown, T C; Jiricny, J (1988). Different base/base mispairs are corrected with different efficiencies and specificities in monkey kidney cells. Cell, 54(5):705-711.

Brown, T C; Jiricny, J (1987). A specific mismatch repair event protects mammalian cells from loss of 5-methylcytosine. Cell, 50(6):945-950.