A Meiotic Checkpoint Alters Repair Partner Bias to Permit Inter-sister Repair of Persistent DSBs

Accurate meiotic chromosome segregation critically depends on the formation of inter-homolog crossovers initiated by double-strand breaks (DSBs). Inaccuracies in this process can drive aneuploidy and developmental defects, but how meiotic cells are protected from unscheduled DNA breaks remains unexplored. Here we define a checkpoint response to persistent meiotic DSBs in C. elegans that phosphorylates the synaptonemal complex (SC) to switch repair partner from the homolog to the sister chromatid. A key target of this response is the core SC component SYP-1, which is phosphorylated in response to ionizing radiation (IR) or unrepaired meiotic DSBs. Failure to phosphorylate (syp-16A) or dephosphorylate (syp-16D) SYP-1 in response to DNA damage results in chromosome non-dysjunction, hyper-sensitivity to IR-induced DSBs, and synthetic lethality with loss of brc-1BRCA1. Since BRC-1 is required for inter-sister repair, these observations reveal that checkpoint-dependent SYP-1 phosphorylation safeguards the germline against persistent meiotic DSBs by channelling repair to the sister chromatid.Cancer Research UK FC0010048UK Medical Research Council FC0010048Wellcome Trust FC0010048Ministerio de Economía y Competitividad BFU2016-75058-PEuropean Research Council ERC2014 AdG669898 TARLOO

Transcription-replication conflicts: How they occur and how they are resolved

The frequent occurrence of transcription and DNA replication in cells results in many encounters, and thus conflicts, between the transcription and replication machineries. These conflicts constitute a major intrinsic source of genome instability, which is a hallmark of cancer cells. How the replication machinery progresses along a DNA molecule occupied by an RNA polymerase is an old question. Here we review recent data on the biological relevance of transcription-replication conflicts, and the factors and mechanisms that are involved in either preventing or resolving them, mainly in eukaryotes. On the basis of these data, we provide our current view of how transcription can generate obstacles to replication, including torsional stress and non-B DNA structures, and of the different cellular processes that have evolved to solve them

Relación entre el ciclo celular y el desarrollo sexual en el hongo causante del carbón del maiz, Ustilago maydis

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 10-04-200

The Caenorhabditis elegans THO Complex Is Required for the Mitotic Cell Cycle and Development

This is an open-access article distributed under the terms of the Creative Commons Attribution License.THO is a conserved eukaryotic complex involved in mRNP biogenesis and RNA export that plays an important role in preventing transcription- and RNA-mediated genome instability in mitosis and meiosis. In mammals THO is essential for embryogenesis, which limits our capacity to analyze the physiological relevance of THO during development and in adult organisms. Using Caenorhabditis elegans as a model system we show that the THO complex is essential for mitotic genome integrity and the developmentally regulated mitotic cell cycles occurring during late postembryonic stages.This work was supported by grants from the Spanish Ministry of Science and Innovation (BFU2010-16372 and Consolider Ingenio 2010 CSD2007-0015), the European Union (FEDER) and the Junta de Andalucía (CVI4567). MCP was the recipient of a predoctoral training fellowship from the Spanish National Institute of Health Carlos III.Peer reviewe

R‐loops cause replication impairment and genome instability during meiosis

R‐loops are harmful structures with a negative impact on transcription and recombination during mitosis, but no information exists for meiosis. We used Saccharomyces cerevisiae and Caenorhabditis elegans THO mutants as a tool to determine the consequences of R‐loops in meiosis. We found that both S. cerevisiae and C. elegans THO mutants show defective meiosis and an impairment of premeiotic replication as well as DNA‐damage accumulation. Importantly, RNase H partially suppressed the replication impairment and the DNA‐damage accumulation. We conclude that R‐loops can form during meiosis causing replication impairment with deleterious results.This work was supported by grants from the Spanish Ministry of Science and Innovation (BFU2006‐05260, BFU2010‐16372 and Consolider Ingenio 2010 CSD2007‐0015), the European Union (FEDER) and the Junta de Andalucía (BIO102 and CVI4567).Peer reviewe

R Loops: From Physiological to Pathological Roles

DNA-RNA hybrids play a physiological role in cellular processes, but often, they represent non-scheduled co-transcriptional structures with a negative impact on transcription, replication and DNA repair. Accumulating evidence suggests that they constitute a source of replication stress, DNA breaks and genome instability. Reciprocally, DNA breaks facilitate DNA-RNA hybrid formation by releasing the double helix torsional conformation. Cells avoid DNA-RNA accumulation by either preventing or removing hybrids directly or by DNA repair-coupled mechanisms. Given the R-loop impact on chromatin and genome organization and its potential relation with genetic diseases, we review R-loop homeostasis as well as their physiological and pathological roles.DNA-RNA hybrids play a physiological role in cellular processes, but often, they represent non-scheduled co-transcriptional structures with a negative impact on transcription, replication and DNA repair. Accumulating evidence suggests that they constitute a source of replication stress, DNA breaks and genome instability. Reciprocally, DNA breaks facilitate DNA-RNA hybrid formation by releasing the double helix torsional conformation. Cells avoid DNA-RNA accumulation by either preventing or removing hybrids directly or by DNA repair-coupled mechanisms. Given the R-loop impact on chromatin and genome organization and its potential relation with genetic diseases, we review R-loop homeostasis as well as their physiological and pathological roles.Research in A.A.’s lab is funded by the European Research Council (ERC2014 AdG669898 TARLOOP), the Spanish Ministry of Economy and Competitiveness (BFU2016-75058-P), the Junta de Andalucía (BIO1238), and the European Union Regional Funds (FEDER)

Transcription-replication conflicts: how they occur and how they are resolved

The frequent occurrence of transcription and DNA replication in cells results in many encounters, and thus conflicts, between the transcription and replication machineries. These conflicts constitute a major intrinsic source of genome instability, which is a hallmark of cancer cells. How the replication machinery progresses along a DNA molecule occupied by an RNA polymerase is an old question. Here we review recent data on the biological relevance of transcription-replication conflicts, and the factors and mechanisms that are involved in either preventing or resolving them, mainly in eukaryotes. On the basis of these data, we provide our current view of how transcription can generate obstacles to replication, including torsional stress and non-B DNA structures, and of the different cellular processes that have evolved to solve them.Research in A.A.’s laboratory is funded by grants from the Spanish Ministry of Economy and Competitiveness, the Junta de Andalucía, the European Union (FEDER), Worldwide Cancer Research and the European Research Council.Peer Reviewe

R Loops: From Transcription Byproducts to Threats to Genome Stability

RNA:DNA hybrid structures known as R loops were thought to be rare byproducts of transcription. In the last decade, however, accumulating evidence has pointed to a new view in which R loops form more frequently, impacting transcription and threatening genome integrity as a source of chromosome fragility and a potential cause of disease. Not surprisingly, cells have evolved mechanisms to prevent cotranscriptional R loop formation. Here we discuss the factors and cellular processes that control R loop formation and the mechanisms by which R loops may influence gene expression and the integrity of the genome.Research in A.A.'s laboratory is funded by the Spanish Ministry of Science and Innovation, Junta de Andalucía, and the European Union (FEDER).Peer reviewe

R Loops: From Physiologicalto Pathological Roles

DNA-RNA hybrids play a physiological role in cellular processes, but often, they represent non-scheduled co-transcriptional structures with a negative impact on transcription, replication and DNA repair. Accumulating evidence suggests that they constitute a source of replication stress, DNA breaks and genome instability. Reciprocally, DNA breaks facilitate DNA-RNA hybrid formation by releasing the double helix torsional conformation. Cells avoid DNA-RNA accumulation by either preventing or removing hybrids directly or by DNA repair-coupled mechanisms. Given the R-loop impact on chromatin and genome organization and its potential relation with genetic diseases, we review R-loop homeostasis as well as their physiological and pathological roles.European Research Council (ERC2014 AdG669898 TARLOOP)Junta de Andalucía (BIO1238)European Union Regional Funds (FEDER