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6. Optical genome mapping identifies structural variants in potentially new cancer predisposition candidate genes in pediatric cancer patients

Author

Wagener, Rabea, primary, Brandes, Danielle, additional, Jung, Marie, additional, Huetzen, Maxim A., additional, Bergmann, Anke K., additional, Panier, Stephanie, additional, Picard, Daniel, additional, Fischer, Ute, additional, Jachimowicz, Ron D., additional, Borkhardt, Arndt, additional, and Brozou, Triantafyllia, additional

Published
2023
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7. Optical genome mapping identifies structural variants in potentially new cancer predisposition candidate genes in pediatric cancer patients.

Author

Wagener, Rabea, Brandes, Danielle, Jung, Marie, Huetzen, Maxim A., Bergmann, Anke K., Panier, Stephanie, Picard, Daniel, Fischer, Ute, Jachimowicz, Ron D., Borkhardt, Arndt, and Brozou, Triantafyllia

Subjects
GENE mapping, CHILDHOOD cancer, CANCER genes, CANCER patients, SINGLE nucleotide polymorphisms, DELETION mutation, CHROMOSOME duplication
Abstract

Genetic predisposition is one of the major risk factors for pediatric cancer, with ~10% of children being carriers of a predisposing germline alteration. It is likely that this is the tip of the iceberg and many children are underdiagnosed, as most of the analysis focuses on single or short nucleotide variants, not considering the full spectrum of DNA alterations. Hence, we applied optical genome mapping (OGM) to our cohort of 34 pediatric cancer patients to perform an unbiased germline screening and analyze the frequency of structural variants (SVs) and their impact on cancer predisposition. All children were clinically highly suspicious for germline alterations (concomitant conditions or congenital anomalies, positive family cancer history, particular cancer type, synchronous or metachronous tumors), but whole exome sequencing (WES) had failed to detect pathogenic variants in cancer predisposing genes. OGM detected a median of 49 rare SVs (range 27‐149) per patient. By analysis of 18 patient‐parent trios, we identified three de novo SVs. Moreover, we discovered a likely pathogenic deletion of exon 3 in the known cancer predisposition gene BRCA2, and identified a duplication in RPA1, which might represent a new cancer predisposition gene. We conclude that optical genome mapping is a suitable tool for detecting potentially predisposing SVs in addition to WES in pediatric cancer patients. [ABSTRACT FROM AUTHOR]

Published
2024
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14. The MMS22L-TONSL Complex Mediates Recovery from Replication Stress and Homologous Recombination

Author

O'Donnell, Lara, Panier, Stephanie, Wildenhain, Jan, Tkach, Johnny M., Al-Hakim, Abdallah, Landry, Marie-Claude, Escribano-Diaz, Cristina, Szilard, Rachel K., Young, Jordan T.F., Munro, Meagan, Canny, Marella D., Kolas, Nadine K., Zhang, Wei, Harding, Shane M., Ylanko, Jarkko, Mendez, Megan, Mullin, Michael, Sun, Thomas, Habermann, Bianca, Datti, Alessandro, Bristow, Robert G., Gingras, Anne-Claude, Tyers, Michael D., Brown, Grant W., and Durocher, Daniel

Published
2010
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16. The RIDDLE Syndrome Protein Mediates a Ubiquitin-Dependent Signaling Cascade at Sites of DNA Damage

Author

Stewart, Grant S., Panier, Stephanie, Townsend, Kelly, Al-Hakim, Abdallah K., Kolas, Nadine K., Miller, Edward S., Nakada, Shinichiro, Ylanko, Jarkko, Olivarius, Signe, Mendez, Megan, Oldreive, Ceri, Wildenhain, Jan, Tagliaferro, Andrea, Pelletier, Laurence, Taubenheim, Nadine, Durandy, Anne, Byrd, Philip J., Stankovic, Tatjana, Taylor, A. Malcolm R., and Durocher, Daniel

Published
2009
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20. Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1

Author

Nakada, Shinichiro, Tai, Ikue, Panier, Stephanie, Al-Hakim, Abdallah, Iemura, Shun-ichiro, Juang, Yu-Chi, O'Donnell, Lara, Kumakubo, Ayako, Munro, Meagan, Sicheri, Frank, Gingras, Anne-Claude, Natsume, Tohru, Suda, Toshio, and Durocher, Daniel

Subjects
Chemical properties, Models, Genetic aspects, Ubiquitin -- Genetic aspects -- Models -- Chemical properties, DNA damage -- Models -- Genetic aspects -- Chemical properties, Amino acids -- Genetic aspects -- Chemical properties -- Models
Abstract

Ubiquitination is a post-translational modification where ubiquitin (Ub), a small polypeptide, is attached to an acceptor amino group, usually on the lysine residue of a substrate (1). Ubiquitination is initiated [...], DNA double-strand breaks (DSBs) pose a potent threat to genome integrity. These lesions also contribute to the efficacy of radiotherapy and many cancer chemotherapeutics. DSBs elicit a signalling cascade that modifies the chromatin surrounding the break, first by ATM-dependent phosphorylation and then by RNF8-, RNF168- and BRCA1-dependent regulatory ubiquitination. Here we report that OTUB1, a deubiquitinating enzyme, is an inhibitor of DSB-induced chromatin ubiquitination. Surprisingly, we found that OTUB1 suppresses RNF168-dependent poly-ubiquitination independently of its catalytic activity. OTUB1 does so by binding to and inhibiting UBC13 (also known as UBE2N), the cognate E2 enzyme for RNF168. This unusual mode of regulation is unlikely to be limited to UBC13 because analysis of OTUB1-associated proteins revealed that OTUB1 binds to E2s of the UBE2D and UBE2E subfamilies. Finally, OTUB1 depletion mitigates the DSB repair defect associated with defective ATM signalling, indicating that pharmacological targeting of the OTUB1-UBC13 interaction might enhance the DNA damage response.

Published
2010

21. New Faces of old Friends: Emerging new Roles of RNA-Binding Proteins in the DNA Double-Strand Break Response

Author

Klaric, Julie A., Wust, Stas, Panier, Stephanie, Klaric, Julie A., Wust, Stas, and Panier, Stephanie

Abstract

DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions. To protect genomic stability and ensure cell homeostasis, cells mount a complex signaling-based response that not only coordinates the repair of the broken DNA strand but also activates cell cycle checkpoints and, if necessary, induces cell death. The last decade has seen a flurry of studies that have identified RNA-binding proteins (RBPs) as novel regulators of the DSB response. While many of these RBPs have well-characterized roles in gene expression, it is becoming increasingly clear that they also have non-canonical functions in the DSB response that go well beyond transcription, splicing and mRNA processing. Here, we review the current understanding of how RBPs are integrated into the cellular response to DSBs and describe how these proteins directly participate in signal transduction, amplification and repair at damaged chromatin. In addition, we discuss the implications of an RBP-mediated DSB response for genome instability and age-associated diseases such as cancer and neurodegeneration.

Published
2021

22. Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase

Author

Kotas, Nadine K., Chapman, J. Ross, Nakada, Shinichiro, Ylanko, Jarkko, Chahwan, Richard, Sweeney, Frederic D., Panier, Stephanie, Mendez, Megan, Wildenhain, Jan, Thomson, Timothy M., Pelletier, Laurence, Jackson, Stephen P., and Durocher, Daniel

Subjects
Ubiquitin -- Genetic aspects, DNA damage -- Physiological aspects
Published
2007

24. The RNF168 paralog RNF169 defines a new class of ubiquitylated histone reader involved in the response to DNA damage

Author

Kitevski-LeBlanc, Julianne, primary, Fradet-Turcotte, Amélie, additional, Kukic, Predrag, additional, Wilson, Marcus D, additional, Portella, Guillem, additional, Yuwen, Tairan, additional, Panier, Stephanie, additional, Duan, Shili, additional, Canny, Marella D, additional, van Ingen, Hugo, additional, Arrowsmith, Cheryl H, additional, Rubinstein, John L, additional, Vendruscolo, Michele, additional, Durocher, Daniel, additional, and Kay, Lewis E, additional

Published
2017
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25. Author response: The RNF168 paralog RNF169 defines a new class of ubiquitylated histone reader involved in the response to DNA damage

Author

Kitevski-LeBlanc, Julianne, primary, Fradet-Turcotte, Amélie, additional, Kukic, Predrag, additional, Wilson, Marcus D, additional, Portella, Guillem, additional, Yuwen, Tairan, additional, Panier, Stephanie, additional, Duan, Shili, additional, Canny, Marella D, additional, van Ingen, Hugo, additional, Arrowsmith, Cheryl H, additional, Rubinstein, John L, additional, Vendruscolo, Michele, additional, Durocher, Daniel, additional, and Kay, Lewis E, additional

Published
2017
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26. The rnf168 paralog rnf169 defines a new class of ubiquitylated histone reader involved in the response to dna damage

Author

Kitevski-Leblanc, Julianne, Fradet-Turcotte, Amélie, Kukic, Predrag, Wilson, Marcus D., Portella, Guillem, Yuwen, Tairan, Panier, Stephanie, Duan, Shili, Canny, Marella D., Van Ingen, Hugo, Arrowsmith, Cheryl H., Rubinstein, John L., Vendruscolo, Michele, Durocher, Daniel, Kay, Lewis E, Kitevski-Leblanc, Julianne, Fradet-Turcotte, Amélie, Kukic, Predrag, Wilson, Marcus D., Portella, Guillem, Yuwen, Tairan, Panier, Stephanie, Duan, Shili, Canny, Marella D., Van Ingen, Hugo, Arrowsmith, Cheryl H., Rubinstein, John L., Vendruscolo, Michele, Durocher, Daniel, and Kay, Lewis E

Published
2017

30. Genomic Instability, Defective Spermatogenesis, Immunodeficiency, and Cancer in a Mouse Model of the RIDDLE Syndrome

Author

Bohgaki, Toshiyuki, primary, Bohgaki, Miyuki, additional, Cardoso, Renato, additional, Panier, Stephanie, additional, Zeegers, Dimphy, additional, Li, Li, additional, Stewart, Grant S., additional, Sanchez, Otto, additional, Hande, M. Prakash, additional, Durocher, Daniel, additional, Hakem, Anne, additional, and Hakem, Razqallah, additional

Published
2011
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32. Double-strand break repair: 53BP1 comes into focus.

Author

Panier, Stephanie and Boulton, Simon J.

Subjects
*DNA, *HOMEOSTASIS, *P53 protein, *DNA-binding proteins, *TELOMERES, *CHROMATIN
Abstract

DNA double-strand break (DSB) signalling and repair is crucial to preserve genomic integrity and maintain cellular homeostasis. p53-binding protein 1 (53BP1) is an important regulator of the cellular response to DSBs that promotes the end-joining of distal DNA ends, which is induced during V(D)J and class switch recombination as well as during the fusion of deprotected telomeres. New insights have been gained into the mechanisms underlying the recruitment of 53BP1 to damaged chromatin and how 53BP1 promotes non-homologous end-joining-mediated DSB repair while preventing homologous recombination. From these studies, a model is emerging in which 53BP1 recruitment requires the direct recognition of a DSB-specific histone code and its influence on pathway choice is mediated by mutual antagonism with breast cancer 1 (BRCA1). [ABSTRACT FROM AUTHOR]

Published
2014
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34. SLX4IP antagonizes promiscuous BLM activity during ALT maintenance

Author

Panier, Stephanie, Maric, Marija, Hewitt, Graeme, Mason-Osann, Emily, Himabindu Gali, Anqi Dai, Labadorf, Adam, Jean-Hugues Guervilly, Ruis, Philip, Segura-Bayona, Sandra, Belan, Ondrej, Marzec, Paulina, Pierre-Henri L Gaillard, Flynn, Rachel L, and Boulton, Simon J

Subjects
Model organisms, Genome Integrity & Repair, Cell Cycle & Chromosomes, Cell Biology, Biochemistry & Proteomics, Genetics & Genomics, digestive system diseases, 3. Good health
Abstract

Cancer cells acquire unlimited proliferative capacity by either re-expressing telomerase or inducing alternative lengthening of telomeres (ALT), which relies on telomere recombination. Here, we show that ALT recombination requires coordinate regulation of the SMX and BTR complexes to ensure the appropriate balance of resolution and dissolution activities at recombining telomeres. Critical to this control is SLX4IP, which accumulates at ALT telomeres and interacts with SLX4, XPF, and BLM. Loss of SLX4IP increases ALT-related phenotypes, which is incompatible with cell growth following concomitant loss of SLX4. Inactivation of BLM is sufficient to rescue telomere aggregation and the synthetic growth defect in this context, suggesting that SLX4IP favors SMX-dependent resolution by antagonizing promiscuous BLM activity during ALT recombination. Finally, we show that SLX4IP is inactivated in a subset of ALT-positive osteosarcomas. Collectively, our findings uncover an SLX4IP-dependent regulatory mechanism critical for telomere maintenance in ALT cancer cells.

35. SLX4IP antagonizes promiscuous BLM activity during ALT maintenance

Author

Panier, Stephanie, Maric, Marija, Hewitt, Graeme, Mason-Osann, Emily, Himabindu Gali, Anqi Dai, Labadorf, Adam, Jean-Hugues Guervilly, Ruis, Philip, Segura-Bayona, Sandra, Belan, Ondrej, Marzec, Paulina, Pierre-Henri L Gaillard, Flynn, Rachel L, and Boulton, Simon J

Subjects
Model organisms, Genome Integrity & Repair, Cell Cycle & Chromosomes, Cell Biology, Biochemistry & Proteomics, Genetics & Genomics, digestive system diseases, 3. Good health
Abstract

Cancer cells acquire unlimited proliferative capacity by either re-expressing telomerase or inducing alternative lengthening of telomeres (ALT), which relies on telomere recombination. Here, we show that ALT recombination requires coordinate regulation of the SMX and BTR complexes to ensure the appropriate balance of resolution and dissolution activities at recombining telomeres. Critical to this control is SLX4IP, which accumulates at ALT telomeres and interacts with SLX4, XPF, and BLM. Loss of SLX4IP increases ALT-related phenotypes, which is incompatible with cell growth following concomitant loss of SLX4. Inactivation of BLM is sufficient to rescue telomere aggregation and the synthetic growth defect in this context, suggesting that SLX4IP favors SMX-dependent resolution by antagonizing promiscuous BLM activity during ALT recombination. Finally, we show that SLX4IP is inactivated in a subset of ALT-positive osteosarcomas. Collectively, our findings uncover an SLX4IP-dependent regulatory mechanism critical for telomere maintenance in ALT cancer cells.

36. The RNF168 paralog RNF169 defines a new class of ubiquitylated histone reader involved in the response to DNA damage

Author

Kitevski-LeBlanc, Julianne, Fradet-Turcotte, Amélie, Kukic, Predrag, Wilson, Marcus D, Portella, Guillem, Yuwen, Tairan, Panier, Stephanie, Duan, Shili, Canny, Marella D, Van Ingen, Hugo, Arrowsmith, Cheryl H, Rubinstein, John L, Vendruscolo, Michele, Durocher, Daniel, and Kay, Lewis E

Subjects
Magnetic Resonance Spectroscopy, D. melanogaster, Ubiquitin-Protein Ligases, Cryoelectron Microscopy, Molecular Dynamics Simulation, 3. Good health, Histones, ubiquitin-based signalling, ubiquitylated-histone reader, biophysics, DNA damage, structural biology, Humans, DNA Breaks, Double-Stranded, human, Protein Binding
Abstract

Site-specific histone ubiquitylation plays a central role in orchestrating the response to DNA double-strand breaks (DSBs). DSBs elicit a cascade of events controlled by the ubiquitin ligase RNF168, which promotes the accumulation of repair factors such as 53BP1 and BRCA1 on the chromatin flanking the break site. RNF168 also promotes its own accumulation, and that of its paralog RNF169, but how they recognize ubiquitylated chromatin is unknown. Using methyl-TROSY solution NMR spectroscopy and molecular dynamics simulations, we present an atomic resolution model of human RNF169 binding to a ubiquitylated nucleosome, and validate it by electron cryomicroscopy. We establish that RNF169 binds to ubiquitylated H2A-Lys13/Lys15 in a manner that involves its canonical ubiquitin-binding helix and a pair of arginine-rich motifs that interact with the nucleosome acidic patch. This three-pronged interaction mechanism is distinct from that by which 53BP1 binds to ubiquitylated H2A-Lys15 highlighting the diversity in site-specific recognition of ubiquitylated nucleosomes.

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