Tatiana García-Muse

Bio: Tatiana García-Muse is an academic researcher from Spanish National Research Council. The author has contributed to research in topics: DNA repair & Genome instability. The author has an hindex of 15, co-authored 22 publications receiving 2794 citations. Previous affiliations of Tatiana García-Muse include University of Cambridge & University of Seville.

Replication stress and cancer

Abstract: Genome instability is a hallmark of cancer, and DNA replication is the most vulnerable cellular process that can lead to it. Any condition leading to high levels of DNA damage will result in replication stress, which is a source of genome instability and a feature of pre-cancerous and cancerous cells. Therefore, understanding the molecular basis of replication stress is crucial to the understanding of tumorigenesis. Although a negative aspect of replication stress is its prominent role in tumorigenesis, a positive aspect is that it provides a potential target for cancer therapy. In this Review, we discuss the link between persistent replication stress and tumorigenesis, with the goal of shedding light on the mechanisms underlying the initiation of an oncogenic process, which should open up new possibilities for cancer diagnostics and treatment.

Causes of Genome Instability

Abstract: Genomes are transmitted faithfully from dividing cells to their offspring. Changes that occur during DNA repair, chromosome duplication, and transmission or via recombination provide a natural source of genetic variation. They occur at low frequency because of the intrinsic variable nature of genomes, which we refer to as genome instability. However, genome instability can be enhanced by exposure to external genotoxic agents or as the result of cellular pathologies. We review the causes of genome instability as well as how it results in hyper-recombination, genome rearrangements, and chromosome fragmentation and loss, which are mainly mediated by double-strand breaks or single-strand gaps. Such events are primarily associated with defects in DNA replication and the DNA damage response, and show high incidence at repetitive DNA, non-B DNA structures, DNA-protein barriers, and highly transcribed regions. Identifying the causes of genome instability is crucial to understanding genome dynamics during cell proliferation and its role in cancer, aging, and a number of rare genetic diseases.

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

Abstract: 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.

Causes and consequences of replication stress.

Abstract: Replication stress is a complex phenomenon that has serious implications for genome stability, cell survival and human disease. Generation of aberrant replication fork structures containing single-stranded DNA activates the replication stress response, primarily mediated by the kinase ATR (ATM- and Rad3-related). Along with its downstream effectors, ATR stabilizes and helps to restart stalled replication forks, avoiding the generation of DNA damage and genome instability. Understanding this response may be key to diagnosing and treating human diseases caused by defective responses to replication stress.

Structure and function of long noncoding RNAs in epigenetic regulation

Abstract: Genomes of complex organisms encode an abundance and diversity of long noncoding RNAs (lncRNAs) that are expressed throughout the cell and fulfill a wide variety of regulatory roles at almost every stage of gene expression. These roles, which encompass sensory, guiding, scaffolding and allosteric capacities, derive from folded modular domains in lncRNAs. In this diverse functional repertoire, we focus on the well-characterized ability for lncRNAs to function as epigenetic modulators. Many lncRNAs bind to chromatin-modifying proteins and recruit their catalytic activity to specific sites in the genome, thereby modulating chromatin states and impacting gene expression. Considering this regulatory potential in combination with the abundance of lncRNAs suggests that lncRNAs may be part of a broad epigenetic regulatory network.

Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications

Abstract: Genome integrity is constantly monitored by sophisticated cellular networks, collectively termed the DNA damage response (DDR). A common feature of DDR proteins is their mobilization in response to genotoxic stress. Here, we outline how the development of various complementary methodologies has provided valuable insights into the spatiotemporal dynamics of DDR protein assembly/disassembly at sites of DNA strand breaks in eukaryotic cells. Considerable advances have also been made in understanding the underlying molecular mechanisms for these events, with post-translational modifications of DDR factors being shown to play prominent roles in controlling the formation of foci in response to DNA-damaging agents. We review these regulatory mechanisms and discuss their biological significance to the DDR.