UMR3348 – Stress génotoxique et cancer

Publications de l’unité

Année de publication : 2018

Maria M Magiera, Puja Singh, Sudarshan Gadadhar, Carsten Janke (2018 May 31)

Tubulin Posttranslational Modifications and Emerging Links to Human Disease.

Cell : 1323-1327 : DOI : 10.1016/j.cell.2018.05.018 En savoir plus

Tubulin posttranslational modifications are currently emerging as important regulators of the microtubule cytoskeleton and thus have a strong potential to be implicated in a number of disorders. Here, we review the latest advances in understanding the physiological roles of tubulin modifications and their links to a variety of pathologies.

Sandrine M Caputo, Mélanie Léone, Francesca Damiola, Asa Ehlen, Aura Carreira, Pascaline Gaidrat, Alexandra Martins, Rita D Brandão, Ana Peixoto, Ana Vega, Claude Houdayer, Capucine Delnatte, Myriam Bronner, Danièle Muller, Laurent Castera, Marine Guillaud-Bataille, Inge Søkilde, Nancy Uhrhammer, Sophie Demontety, Hélène Tubeuf, Gaïa Castelain, , Uffe Birk Jensen, Ambre Petitalot, Sophie Krieger, Cédrick Lefol, Virginie Moncoutier, Nadia Boutry-Kryza, Henriette Roed Nielsen, Olga Sinilnikova, Dominique Stoppa-Lyonnet, Amanda B Spurdle, Manuel R Teixeira, Florence Coulet, Mads Thomassen, Etienne Rouleau (2018 Apr 3)

Full in-frame exon 3 skipping of BRCA2 confers high risk of breast and/or ovarian cancer.

Oncotarget : 17334-17348 : DOI : 10.18632/oncotarget.24671 En savoir plus

Germline pathogenic variants in the gene are associated with a cumulative high risk of breast/ovarian cancer. Several variants result in complete loss of the exon-3 at the transcript level. The pathogenicity of these variants and the functional impact of loss of exon 3 have yet to be established. As a collaboration of the COVAR clinical trial group (France), and the ENIGMA consortium for investigating breast cancer gene variants, this study evaluated 8 variants resulting in complete deletion of exon 3. Clinical information for 39 families was gathered from Portugal, France, Denmark and Sweden. Multifactorial likelihood analyses were conducted using information from 293 patients, for 7 out of the 8 variants (including 6 intronic). For all variants combined the likelihood ratio in favor of causality was 4.39*10. These results provide convincing evidence for the pathogenicity of all examined variants that lead to a total exon 3 skipping, and suggest that other variants that result in complete loss of exon 3 at the molecular level could be associated with a high risk of cancer comparable to that associated with classical pathogenic variants in or gene. In addition, our functional study shows, for the first time, that deletion of exon 3 impairs the ability of cells to survive upon Mitomycin-C treatment, supporting lack of function for the altered BRCA2 protein in these cells. Finally, this study demonstrates that any variant leading to expression of only delta-exon 3 will be associated with an increased risk of breast and ovarian cancer.

Catharina von Nicolai, Åsa Ehlén, Juan S Martinez, Aura Carreira (2018 Apr 1)

Dissecting the Recombination Mediator Activity of BRCA2 Using Biochemical Methods.

Methods in enzymology : 479-511 : DOI : S0076-6879(17)30356-7 En savoir plus

Homologous recombination (HR) is an essential pathway to restart stalled replication forks, repair spontaneous DNA double-strand breaks, and generate genetic diversity. Together with genetic studies in model organisms, the development of purification protocols and biochemical assays has allowed investigators to begin to understand how the complex machinery of HR functions. At the core of the HR process is the recombination enzyme RecA in bacteria or RAD51 and DMC1 in eukaryotes. The main steps of HR can be reconstituted in vitro and involve: (1) The formation of a ssDNA-RAD51 complex into a helical structure termed the nucleoprotein filament after one DNA strand has been resected at the site of the break. (2) The homologous DNA pairing with an intact copy of the damaged chromatid to form a joint molecule also called displacement loop (D-loop). (3) The exchange of DNA strands and de novo DNA synthesis to restore the damaged/lost DNA. (4) The resolution of joint molecules by nucleolytic cleavage. The human tumor suppressor BRCA2 is a mediator of HR as it actively facilitates the DNA transactions of the recombination proteins RAD51 and DMC1 in a variety of ways: It stabilizes ssDNA-RAD51/DMC1 nucleoprotein filaments. It limits the assembly of RAD51 on dsDNA. It facilitates the replacement of replication protein A by RAD51. The result of these activities is a net increase of DNA strand exchange products as observed in vitro. Here, we describe some of the biochemical assays used to dissect the mediator activities of BRCA2.

Sanchita Bhattacharya, Jian Li, Alexandra Sockell, Matthew J Kan, Felice A Bava, Shann-Ching Chen, María C Ávila-Arcos, Xuhuai Ji, Emery Smith, Narges B Asadi, Ralph S Lachman, Hugo Y K Lam, Carlos D Bustamante, Atul J Butte, Garry P Nolan (2018 Apr 1)

Whole-genome sequencing of Atacama skeleton shows novel mutations linked with dysplasia.

Genome research : 423-431 : DOI : 10.1101/gr.223693.117 En savoir plus

Over a decade ago, the Atacama humanoid skeleton (Ata) was discovered in the Atacama region of Chile. The Ata specimen carried a strange phenotype-6-in stature, fewer than expected ribs, elongated cranium, and accelerated bone age-leading to speculation that this was a preserved nonhuman primate, human fetus harboring genetic mutations, or even an extraterrestrial. We previously reported that it was human by DNA analysis with an estimated bone age of about 6-8 yr at the time of demise. To determine the possible genetic drivers of the observed morphology, DNA from the specimen was subjected to whole-genome sequencing using the Illumina HiSeq platform with an average 11.5× coverage of 101-bp, paired-end reads. In total, 3,356,569 single nucleotide variations (SNVs) were found as compared to the human reference genome, 518,365 insertions and deletions (indels), and 1047 structural variations (SVs) were detected. Here, we present the detailed whole-genome analysis showing that Ata is a female of human origin, likely of Chilean descent, and its genome harbors mutations in genes (, , , , , , ) previously linked with diseases of small stature, rib anomalies, cranial malformations, premature joint fusion, and osteochondrodysplasia (also known as skeletal dysplasia). Together, these findings provide a molecular characterization of Ata’s peculiar phenotype, which likely results from multiple known and novel putative gene mutations affecting bone development and ossification.