Suchergebnisse

It has been long known that some regions of the genome are more susceptible to damage and mutagenicity than others. Recent advances have determined a critical role of chromatin both in the incidence of damage and in its repair. Thus, chromatin arises as a guardian of the stability of the genome, which is altered in cancer cells. In this review, we focus into the mechanisms by which chromatin influences the occurrence and repair of the most cytotoxic DNA lesions, double-strand breaks, in particular at actively transcribed chromatin or related to DNA replication. ; Research in AA's lab is funded by the European Research Council, the Spanish Ministry of Economy and Competitiveness, Junta de Andalucía and the European Union (FEDER).

This is an open-access article distributed under the terms of the Creative Commons Attribution License. ; THO/TREX connects transcription with genome integrity in yeast, but a role of mammalian THO in these processes is uncertain, which suggests a differential implication of mRNP biogenesis factors in genome integrity in yeast and humans. We show that human THO depletion impairs transcription elongation and mRNA export and increases instability associated with DNA breaks, leading to hyper-recombination and γH2AX and 53BP1 foci accumulation. This is accompanied by replication alteration as determined by DNA combing. Genome instability is R-loop–dependent, as deduced from the ability of the AID enzyme to increase DNA damage and of RNaseH to reduce it, or from the enhancement of R-loop–dependent class-switching caused by THOC1-depletion in CH12 murine cells. Therefore, mammalian THO prevents R-loop formation and has a role in genome dynamics and function consistent with an evolutionary conservation of the functional connection between these mRNP biogenesis factors and genome integrity that had not been anticipated. ; This work was funded by grants from the Spanish Ministry of Science and Innovation (BFU2006-05260, BFU2010-16372, and Consolider Ingenio 2010 CSD2007-015), the Junta de Andalucía (BIO102, CVI624, and CVI4567), and the European Union (FEDER). ; Peer reviewed

DNA:RNA hybrids constitute a well-known source of recombinogenic DNA damage. The current literature is in agreement with DNA:RNA hybrids being produced co-transcriptionally by the invasion of the nascent RNA molecule produced in cis with its DNA template. However, it has also been suggested that recombinogenic DNA:RNA hybrids could be facilitated by the invasion of RNA molecules produced in trans in a Rad51-mediated reaction. Here, we tested the possibility that such DNA:RNA hybrids constitute a source of recombinogenic DNA damage taking advantage of Rad51-independent single-strand annealing (SSA) assays in the yeast Saccharomyces cerevisiae. For this, we used new constructs designed to induce expression of mRNA transcripts in trans with respect to the SSA system. We show that unscheduled and recombinogenic DNA:RNA hybrids that trigger the SSA event are formed in cis during transcription and in a Rad51-independent manner. We found no evidence that such hybrids form in trans and in a Rad51-dependent manner. ; Research was supported by the Spanish Ministry of Economy and Competitiveness (BFU2016-75058- P) and the European Union (FEDER). BG-G was funded by a grant from the Spanish Association Against Cancer (AECC).

The stability and function of eukaryotic genomes is closely linked to histones and to chromatin structure. The state of the chromatin not only affects the probability of DNA to undergo damage but also DNA repair. DNA damage can result in genetic alterations and subsequent development of cancer and other genetic diseases. Here, we identified two mutations in conserved residues of histone H3 and histone H4 (H3E73Q and H4E53A) that increase recombinogenic DNA damage. Our results suggest that the accumulation of DNA damage in these histone mutants is largely independent on transcription and might arise as a consequence of problems occurring during DNA replication. This study uncovers the relevance of H3E73 and H4E53 residues in the protection of genome integrity. ; Research was supported by the European Research Council (ERC2014 AdG669898 TARLOOP), the Spanish Ministry of Economy and Competitiveness (BFU2016-75058-P), the Foundation Vencer el Cáncer and the European Union (FEDER). P. O. was supported by a predoctoral training grant from the Spanish Ministry of Economy and Competitiveness and B.G.-G. by the Span-ish Association Against Cancer (AECC).

The stability and function of eukaryotic genomes is closely linked to histones and to chromatin structure. The state of the chromatin not only affects the probability of DNA to undergo damage but also DNA repair. DNA damage can result in genetic alterations and subsequent development of cancer and other genetic diseases. Here, we identified two mutations in conserved residues of histone H3 and histone H4 (H3E73Q and H4E53A) that increase recombinogenic DNA damage. Our results suggest that the accumulation of DNA damage in these histone mutants is largely independent on transcription and might arise as a consequence of problems occurring during DNA replication. This study uncovers the relevance of H3E73 and H4E53 residues in the protection of genome integrity. ; Research was supported by the Euro-pean Research Council (ERC2014 AdG669898 TARLOOP), the Spanish Ministry of Economy and Competitiveness (BFU2016-75058-P), the Foundation Vencer el Cáncer and the European Union (FEDER). P. O. was supported by a predoctoral training grant from the Spanish Ministry of Economy and Competitiveness and B.G.-G. by the Span-ish Association Against Cancer (AECC). ; Yes