Project acronym AAMDDR
Project DNA damage response and genome stability: The role of ATM, ATR and the Mre11 complex
Researcher (PI) Vincenzo Costanzo
Host Institution (HI) CANCER RESEARCH UK LBG
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary Chromosomal DNA is continuously subjected to exogenous and endogenous damaging insults. In the presence of DNA damage cells activate a multi-faceted checkpoint response that delays cell cycle progression and promotes DNA repair. Failures in this response lead to genomic instability, the main feature of cancer cells. Several cancer-prone human syndromes including the Ataxia teleangiectasia (A-T), the A-T Like Disorder (ATLD) and the Seckel Syndrome reflect defects in the specific genes of the DNA damage response such as ATM, MRE11 and ATR. DNA damage response pathways are poorly understood at biochemical level in vertebrate organisms. We have established a cell-free system based on Xenopus laevis egg extract to study molecular events underlying DNA damage response. This is the first in vitro system that recapitulates different aspects of the DNA damage response in vertebrates. Using this system we propose to study the biochemistry of the ATM, ATR and the Mre11 complex dependent DNA damage response. In particular we will: 1) Dissect the signal transduction pathway that senses DNA damage and promotes cell cycle arrest and DNA damage repair; 2) Analyze at molecular level the role of ATM, ATR, Mre11 in chromosomal DNA replication and mitosis during normal and stressful conditions; 3) Identify substrates of the ATM and ATR dependent DNA damage response using an innovative screening procedure.
Summary
Chromosomal DNA is continuously subjected to exogenous and endogenous damaging insults. In the presence of DNA damage cells activate a multi-faceted checkpoint response that delays cell cycle progression and promotes DNA repair. Failures in this response lead to genomic instability, the main feature of cancer cells. Several cancer-prone human syndromes including the Ataxia teleangiectasia (A-T), the A-T Like Disorder (ATLD) and the Seckel Syndrome reflect defects in the specific genes of the DNA damage response such as ATM, MRE11 and ATR. DNA damage response pathways are poorly understood at biochemical level in vertebrate organisms. We have established a cell-free system based on Xenopus laevis egg extract to study molecular events underlying DNA damage response. This is the first in vitro system that recapitulates different aspects of the DNA damage response in vertebrates. Using this system we propose to study the biochemistry of the ATM, ATR and the Mre11 complex dependent DNA damage response. In particular we will: 1) Dissect the signal transduction pathway that senses DNA damage and promotes cell cycle arrest and DNA damage repair; 2) Analyze at molecular level the role of ATM, ATR, Mre11 in chromosomal DNA replication and mitosis during normal and stressful conditions; 3) Identify substrates of the ATM and ATR dependent DNA damage response using an innovative screening procedure.
Max ERC Funding
1 000 000 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym ARISTOTLE
Project Aristotle in the Italian Vernacular: Rethinking Renaissance and Early-Modern Intellectual History (c. 1400–c. 1650)
Researcher (PI) Marco Sgarbi
Host Institution (HI) UNIVERSITA CA' FOSCARI VENEZIA
Call Details Starting Grant (StG), SH5, ERC-2013-StG
Summary From the twelfth to the seventeenth century, Aristotle’s writings lay at the foundation of Western culture, providing a body of knowledge and a set of analytical tools applicable to all areas of human investigation. Scholars of the Renaissance have emphasized the remarkable longevity and versatility of Aristotelianism, but their attention has remained firmly, and almost exclusively, fixed on the transmission of Aristotle’s works in Latin. Scarce attention has gone to works in the vernacular. Nonetheless, several important Renaissance figures wished to make Aristotle’s works accessible and available outside the narrow circle of professional philosophers and university professors. They believed that his works could provide essential knowledge to a broad set of readers, and embarked on an intense programme of translation and commentary to see this happen. It is the argument of this project that vernacular Aristotelianism made fundamental contributions to the thought of the period, anticipating many of the features of early modern philosophy and contributing to a new encyclopaedia of knowledge. Our project aims to offer the first detailed and comprehensive study of the vernacular diffusion of Aristotle through a series of analyses of its main texts. We will thus study works that fall within the two main Renaissance divisions of speculative philosophy (metaphysics, natural philosophy, mathematics, and logic) and civil philosophy (ethics, politics, rhetoric, and poetics). We will give strong attention to the contextualization of the texts they examine, as is standard practice in the best kind of intellectual history, focusing on institutional contexts, reading publics, the value of the vernacular, new visions of knowledge and eclecticism. With the work of the PI, two professors, 5 post-docs and two PhD students we aim to make considerable advances in the understanding of both speculative and civil philosophy within vernacular Aristotelianism.
Summary
From the twelfth to the seventeenth century, Aristotle’s writings lay at the foundation of Western culture, providing a body of knowledge and a set of analytical tools applicable to all areas of human investigation. Scholars of the Renaissance have emphasized the remarkable longevity and versatility of Aristotelianism, but their attention has remained firmly, and almost exclusively, fixed on the transmission of Aristotle’s works in Latin. Scarce attention has gone to works in the vernacular. Nonetheless, several important Renaissance figures wished to make Aristotle’s works accessible and available outside the narrow circle of professional philosophers and university professors. They believed that his works could provide essential knowledge to a broad set of readers, and embarked on an intense programme of translation and commentary to see this happen. It is the argument of this project that vernacular Aristotelianism made fundamental contributions to the thought of the period, anticipating many of the features of early modern philosophy and contributing to a new encyclopaedia of knowledge. Our project aims to offer the first detailed and comprehensive study of the vernacular diffusion of Aristotle through a series of analyses of its main texts. We will thus study works that fall within the two main Renaissance divisions of speculative philosophy (metaphysics, natural philosophy, mathematics, and logic) and civil philosophy (ethics, politics, rhetoric, and poetics). We will give strong attention to the contextualization of the texts they examine, as is standard practice in the best kind of intellectual history, focusing on institutional contexts, reading publics, the value of the vernacular, new visions of knowledge and eclecticism. With the work of the PI, two professors, 5 post-docs and two PhD students we aim to make considerable advances in the understanding of both speculative and civil philosophy within vernacular Aristotelianism.
Max ERC Funding
1 483 180 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym ARSEM
Project LANGUAGE–PHILOLOGY–CULTURE: Arab Cultural Semantics in Transition
Researcher (PI) Kirill Dmitriev
Host Institution (HI) THE UNIVERSITY COURT OF THE UNIVERSITY OF ST ANDREWS
Call Details Starting Grant (StG), SH5, ERC-2012-StG_20111124
Summary This project aims to study:
• the semantic development of the vocabulary of the Arabic language,
• philological discourses on the semantic changes in the language in the classical Arabic philological tradition (8th-10th centuries A.D.), and
• the impact of Arabic philology in the wider historical and cultural context of the Judaeo-Arab neo-classical heritage (12th-13th centuries A.D.) and Christian-Arab intellectual history on the eve of modernity (19th century A.D.).
The project will explore the universal cultural significance and the pivotal role of language consciousness in the history of Arab culture. It will introduce a new dimension into the existing research on the Arabic language and Arabic philology, which until now have been studied without any comprehensive cultural and social contextualisation. The project will focus on the process of the transmission of Arabic poetry, which provides detailed evidence of the development of Arabic philological thought and its universal significance for the theological, philosophical, historical and linguistic discourses of Arab intellectual history. This project will document the transmission of early Arabic poetry and analyse its vocabulary in a systematic way for the first time. For this purpose it will create an Analytical Database of Arabic Poetry. This publicly accessible database will represent a ground-breaking contribution to European research on the Arabic language and the Arabic philological heritage, which so far lacks even such fundamental tools as an etymological dictionary of the Arabic language or a complete dictionary of Classical Arabic. The database will implement comprehensive analytical tools and will serve as a reference work for wider research on Arabic literature, history and culture. Thus, the project will create an integrative research platform for the history and semantics of the Arabic language—a subject indispensable for understanding the foundations of Arab culture past and present.
Summary
This project aims to study:
• the semantic development of the vocabulary of the Arabic language,
• philological discourses on the semantic changes in the language in the classical Arabic philological tradition (8th-10th centuries A.D.), and
• the impact of Arabic philology in the wider historical and cultural context of the Judaeo-Arab neo-classical heritage (12th-13th centuries A.D.) and Christian-Arab intellectual history on the eve of modernity (19th century A.D.).
The project will explore the universal cultural significance and the pivotal role of language consciousness in the history of Arab culture. It will introduce a new dimension into the existing research on the Arabic language and Arabic philology, which until now have been studied without any comprehensive cultural and social contextualisation. The project will focus on the process of the transmission of Arabic poetry, which provides detailed evidence of the development of Arabic philological thought and its universal significance for the theological, philosophical, historical and linguistic discourses of Arab intellectual history. This project will document the transmission of early Arabic poetry and analyse its vocabulary in a systematic way for the first time. For this purpose it will create an Analytical Database of Arabic Poetry. This publicly accessible database will represent a ground-breaking contribution to European research on the Arabic language and the Arabic philological heritage, which so far lacks even such fundamental tools as an etymological dictionary of the Arabic language or a complete dictionary of Classical Arabic. The database will implement comprehensive analytical tools and will serve as a reference work for wider research on Arabic literature, history and culture. Thus, the project will create an integrative research platform for the history and semantics of the Arabic language—a subject indispensable for understanding the foundations of Arab culture past and present.
Max ERC Funding
1 499 507 €
Duration
Start date: 2013-02-01, End date: 2019-01-31
Project acronym ATMINDDR
Project ATMINistrating ATM signalling: exploring the significance of ATM regulation by ATMIN
Researcher (PI) Axel Behrens
Host Institution (HI) THE FRANCIS CRICK INSTITUTE LIMITED
Call Details Starting Grant (StG), LS1, ERC-2011-StG_20101109
Summary ATM is the protein kinase that is mutated in the hereditary autosomal recessive disease ataxia telangiectasia (A-T). A-T patients display immune deficiencies, cancer predisposition and radiosensitivity. The molecular role of ATM is to respond to DNA damage by phosphorylating its substrates, thereby promoting repair of damage or arresting the cell cycle. Following the induction of double-strand breaks (DSBs), the NBS1 protein is required for activation of ATM. But ATM can also be activated in the absence of DNA damage. Treatment of cultured cells with hypotonic stress leads to the activation of ATM, presumably due to changes in chromatin structure. We have recently described a second ATM cofactor, ATMIN (ATM INteractor). ATMIN is dispensable for DSBs-induced ATM signalling, but ATM activation following hypotonic stress is mediated by ATMIN. While the biological role of ATM activation by DSBs and NBS1 is well established, the significance, if any, of ATM activation by ATMIN and changes in chromatin was up to now completely enigmatic.
ATM is required for class switch recombination (CSR) and the suppression of translocations in B cells. In order to determine whether ATMIN is required for any of the physiological functions of ATM, we generated a conditional knock-out mouse model for ATMIN. ATM signaling was dramatically reduced following osmotic stress in ATMIN-mutant B cells. ATMIN deficiency led to impaired CSR, and consequently ATMIN-mutant mice developed B cell lymphomas. Thus ablation of ATMIN resulted in a severe defect in ATM function. Our data strongly argue for the existence of a second NBS1-independent mode of ATM activation that is physiologically relevant. While a large amount of scientific effort has gone into characterising ATM signaling triggered by DSBs, essentially nothing is known about NBS1-independent ATM signaling. The experiments outlined in this proposal have the aim to identify and understand the molecular pathway of ATMIN-dependent ATM signaling.
Summary
ATM is the protein kinase that is mutated in the hereditary autosomal recessive disease ataxia telangiectasia (A-T). A-T patients display immune deficiencies, cancer predisposition and radiosensitivity. The molecular role of ATM is to respond to DNA damage by phosphorylating its substrates, thereby promoting repair of damage or arresting the cell cycle. Following the induction of double-strand breaks (DSBs), the NBS1 protein is required for activation of ATM. But ATM can also be activated in the absence of DNA damage. Treatment of cultured cells with hypotonic stress leads to the activation of ATM, presumably due to changes in chromatin structure. We have recently described a second ATM cofactor, ATMIN (ATM INteractor). ATMIN is dispensable for DSBs-induced ATM signalling, but ATM activation following hypotonic stress is mediated by ATMIN. While the biological role of ATM activation by DSBs and NBS1 is well established, the significance, if any, of ATM activation by ATMIN and changes in chromatin was up to now completely enigmatic.
ATM is required for class switch recombination (CSR) and the suppression of translocations in B cells. In order to determine whether ATMIN is required for any of the physiological functions of ATM, we generated a conditional knock-out mouse model for ATMIN. ATM signaling was dramatically reduced following osmotic stress in ATMIN-mutant B cells. ATMIN deficiency led to impaired CSR, and consequently ATMIN-mutant mice developed B cell lymphomas. Thus ablation of ATMIN resulted in a severe defect in ATM function. Our data strongly argue for the existence of a second NBS1-independent mode of ATM activation that is physiologically relevant. While a large amount of scientific effort has gone into characterising ATM signaling triggered by DSBs, essentially nothing is known about NBS1-independent ATM signaling. The experiments outlined in this proposal have the aim to identify and understand the molecular pathway of ATMIN-dependent ATM signaling.
Max ERC Funding
1 499 881 €
Duration
Start date: 2012-02-01, End date: 2018-01-31
Project acronym BEYONDENEMYLINES
Project Beyond Enemy Lines: Literature and Film in the British and American Zones of Occupied Germany, 1945-1949
Researcher (PI) Lara Feigel
Host Institution (HI) KING'S COLLEGE LONDON
Call Details Starting Grant (StG), SH5, ERC-2013-StG
Summary This project investigates the cross-fertilisation of Anglo/American and German literature and film during the Allied Occupation of Germany. It will be the first study to survey the cultural landscape of the British and American zones of Occupied Germany in any detail. By doing so it will offer a new interpretative framework for postwar culture, in particular in three areas: the history of the Allied Occupation of Germany; the history of postwar Anglophone and Germanophone literature (arguing the two were more intertwined than has previously been suggested); and the history of the relationship between postwar and Cold War. Combining Anglo-American and German literature and film history with critical analysis, cultural history and life-writing, this is a necessarily ambitious, multidisciplinary study which will open up a major new field of research.
Summary
This project investigates the cross-fertilisation of Anglo/American and German literature and film during the Allied Occupation of Germany. It will be the first study to survey the cultural landscape of the British and American zones of Occupied Germany in any detail. By doing so it will offer a new interpretative framework for postwar culture, in particular in three areas: the history of the Allied Occupation of Germany; the history of postwar Anglophone and Germanophone literature (arguing the two were more intertwined than has previously been suggested); and the history of the relationship between postwar and Cold War. Combining Anglo-American and German literature and film history with critical analysis, cultural history and life-writing, this is a necessarily ambitious, multidisciplinary study which will open up a major new field of research.
Max ERC Funding
1 414 601 €
Duration
Start date: 2013-09-01, End date: 2019-02-28
Project acronym BIFLOW
Project Bilingualism in Florentine and Tuscan Works (ca. 1260 - ca. 1416)
Researcher (PI) Antonio Montefusco
Host Institution (HI) UNIVERSITA CA' FOSCARI VENEZIA
Call Details Starting Grant (StG), SH5, ERC-2014-STG
Summary This project will undertake the first systematic investigation of the various literary documents that circulated simultaneously in more than one language in Tuscany, and especially Florence, between the mid-13th Century and the beginning of 15th Century.
During that period, Florence was both a prominent literary centre in the vernacular, and home to a renewal of classical Latin eloquence. While both fields are well studied, their interaction remains largely unexplored. This research, at the convergence of several disciplines (literature, philology, linguistics and medieval history), has a strong pioneering character. It aims at changing the perception of medieval Italian culture and interpretation of the break between medieval Culture and Humanism.
For this reason, the project will develop research in varying degrees of depth. First, it will provide the first catalogue of bilingual texts and manuscripts of medieval Tuscany. Organized as a database, this tool of analysis will stir innovative research in this field, some of which will be immediately promoted during the project.
Secondly, two case studies, considered as important and methodologically exemplary, will be researched in detail, through the publication of two important set of texts, of secular and religious nature : 1. The vernacular translation of the Latin Epistles of Dante Alighieri; 2. A collection of polemical, historiographical, devotional and prophetical documents produced by the Tuscan dissident Franciscans in last decades of the 14th Century.
Finally, the entire team, led by the PI, will be involved in the preparation of a synthesis volume on Tuscan culture in the fourteenth century viewed through bilingualism, entitled Cartography of bilingual culture in Fourteenth-Century Tuscany. From this general map of the Italian culture of the time, no literary genre nor field (be it religious or lay) shall be excluded.
Summary
This project will undertake the first systematic investigation of the various literary documents that circulated simultaneously in more than one language in Tuscany, and especially Florence, between the mid-13th Century and the beginning of 15th Century.
During that period, Florence was both a prominent literary centre in the vernacular, and home to a renewal of classical Latin eloquence. While both fields are well studied, their interaction remains largely unexplored. This research, at the convergence of several disciplines (literature, philology, linguistics and medieval history), has a strong pioneering character. It aims at changing the perception of medieval Italian culture and interpretation of the break between medieval Culture and Humanism.
For this reason, the project will develop research in varying degrees of depth. First, it will provide the first catalogue of bilingual texts and manuscripts of medieval Tuscany. Organized as a database, this tool of analysis will stir innovative research in this field, some of which will be immediately promoted during the project.
Secondly, two case studies, considered as important and methodologically exemplary, will be researched in detail, through the publication of two important set of texts, of secular and religious nature : 1. The vernacular translation of the Latin Epistles of Dante Alighieri; 2. A collection of polemical, historiographical, devotional and prophetical documents produced by the Tuscan dissident Franciscans in last decades of the 14th Century.
Finally, the entire team, led by the PI, will be involved in the preparation of a synthesis volume on Tuscan culture in the fourteenth century viewed through bilingualism, entitled Cartography of bilingual culture in Fourteenth-Century Tuscany. From this general map of the Italian culture of the time, no literary genre nor field (be it religious or lay) shall be excluded.
Max ERC Funding
1 480 625 €
Duration
Start date: 2015-10-01, End date: 2020-09-30
Project acronym BUMP
Project BETTER UNDERSTANDING the METAPHYSICS of PREGNANCY
Researcher (PI) Elisabeth Marjolijn Kingma
Host Institution (HI) UNIVERSITY OF SOUTHAMPTON
Call Details Starting Grant (StG), SH5, ERC-2015-STG
Summary Every single human is the product of a pregnancy: an approximately nine-month period during which a foetus develops within its mother’s body. Yet pregnancy has not been a traditional focus in philosophy. That is remarkable, for two reasons:
First, because pregnancy presents fascinating philosophical problems: what, during the pregnancy, is the nature of the relationship between the foetus and the maternal organism? What is the relationship between the pregnant organism and the later baby? And when does one person or organism become two?
Second, because so many topics immediately adjacent to or involved in pregnancy have taken centre stage in philosophical enquiry. Examples include questions about personhood, foetuses, personal identity and the self.
This project launches the metaphysics of pregnancy as an important and fundamental area of philosophical research.
The core aims of the project are:
(1) to develop a philosophically sophisticated account of human pregnancy and birth, and the entities involved in this, that is attentive to our best empirical understanding of human reproductive biology;
(2) to articulate the metaphysics of organisms, persons and selves in a way that acknowledges the details of how we come into existence; and
(3) to start the process of rewriting the legal, social and moral language we use to classify ourselves and our actions, so that it is compatible with and can accommodate the nature of pregnancy.
The project will investigate these questions in the context of a range of philosophical sub disciplines, including analytic metaphysics, philosophy of biology and feminist philosophy, and in close dialogue with our best empirical understanding of the life sciences – most notably physiology.
Summary
Every single human is the product of a pregnancy: an approximately nine-month period during which a foetus develops within its mother’s body. Yet pregnancy has not been a traditional focus in philosophy. That is remarkable, for two reasons:
First, because pregnancy presents fascinating philosophical problems: what, during the pregnancy, is the nature of the relationship between the foetus and the maternal organism? What is the relationship between the pregnant organism and the later baby? And when does one person or organism become two?
Second, because so many topics immediately adjacent to or involved in pregnancy have taken centre stage in philosophical enquiry. Examples include questions about personhood, foetuses, personal identity and the self.
This project launches the metaphysics of pregnancy as an important and fundamental area of philosophical research.
The core aims of the project are:
(1) to develop a philosophically sophisticated account of human pregnancy and birth, and the entities involved in this, that is attentive to our best empirical understanding of human reproductive biology;
(2) to articulate the metaphysics of organisms, persons and selves in a way that acknowledges the details of how we come into existence; and
(3) to start the process of rewriting the legal, social and moral language we use to classify ourselves and our actions, so that it is compatible with and can accommodate the nature of pregnancy.
The project will investigate these questions in the context of a range of philosophical sub disciplines, including analytic metaphysics, philosophy of biology and feminist philosophy, and in close dialogue with our best empirical understanding of the life sciences – most notably physiology.
Max ERC Funding
1 273 290 €
Duration
Start date: 2016-04-01, End date: 2021-03-31
Project acronym CHARTING THE DIGITAL
Project Charting the Digital: Digital Mapping Practices as New Media Cultures
Researcher (PI) Sybille Lammes
Host Institution (HI) THE UNIVERSITY OF WARWICK
Call Details Starting Grant (StG), SH5, ERC-2011-StG_20101124
Summary Maps have changed and with that our sense of space and spatial awareness. The key objective of this research programme is to develop a framework for the conceptualization of digital maps as new techno-cultural phenomena. Digital maps allow a greater degree of interaction between users and mapping interfaces than analogue maps do. Instead of just reading maps, users have far more influence on how maps look. Whether a navigation device that adjusts its route-display according to where the driver chooses to go, or a map in a computer-game that is partly created by players, maps have become more interactive and are now co-produced by their users.
With this ERC starting grant I propose to build up a new research programme to investigate what this shift entails. I will do so by conducting a comparative analysis of a broad spectrum of digital mapping devices: in relation to (a) each other, (b) traditional cartography and (c) to other media forms that are concerned with mapping and navigation.
This research programme will yield new results on how digital maps can be simultaneously understood as new media, technologies and cartographies by using a unique combination of perspectives from New Media Studies, Science and Technologies Studies. It will also contribute to a recently emerging discussion in which new media are conceived as material cultures that are physically embedded in daily life, countering conventional views of them as just new, virtual and ‘out there’. Digital maps underscore all the main assertions that figure in this recent ‘material turn’ at once: they remediate existing spaces, they merge virtual and physical spaces and are locally used and appropriated yet at the same time products of a global culture. This study will thus break new ground by offering New Media Studies innovative ways for understanding materiality, spatiality and technology.
Summary
Maps have changed and with that our sense of space and spatial awareness. The key objective of this research programme is to develop a framework for the conceptualization of digital maps as new techno-cultural phenomena. Digital maps allow a greater degree of interaction between users and mapping interfaces than analogue maps do. Instead of just reading maps, users have far more influence on how maps look. Whether a navigation device that adjusts its route-display according to where the driver chooses to go, or a map in a computer-game that is partly created by players, maps have become more interactive and are now co-produced by their users.
With this ERC starting grant I propose to build up a new research programme to investigate what this shift entails. I will do so by conducting a comparative analysis of a broad spectrum of digital mapping devices: in relation to (a) each other, (b) traditional cartography and (c) to other media forms that are concerned with mapping and navigation.
This research programme will yield new results on how digital maps can be simultaneously understood as new media, technologies and cartographies by using a unique combination of perspectives from New Media Studies, Science and Technologies Studies. It will also contribute to a recently emerging discussion in which new media are conceived as material cultures that are physically embedded in daily life, countering conventional views of them as just new, virtual and ‘out there’. Digital maps underscore all the main assertions that figure in this recent ‘material turn’ at once: they remediate existing spaces, they merge virtual and physical spaces and are locally used and appropriated yet at the same time products of a global culture. This study will thus break new ground by offering New Media Studies innovative ways for understanding materiality, spatiality and technology.
Max ERC Funding
1 422 453 €
Duration
Start date: 2011-11-01, End date: 2016-10-31
Project acronym CHROMOSOME STABILITY
Project Coordination of DNA replication and DNA repair at single-forks: the role of the Smc5-Smc6 complex in replication fork stalling and resumption
Researcher (PI) Luis Fernando Aragon Alcaide
Host Institution (HI) IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary DNA replication represents a dangerous moment in the life of the cell as endogenous and exogenous events challenge genome integrity by interfering with the progression, stability and restart of the replication fork. Failure to protect stalled forks or to process the replication fork appropriately contribute to the pathological mechanisms giving rise to cancer, therefore an understanding of the intricate mechanisms that ensure fork integrity can provide targets for new chemotherapeutic assays. Smc5-Smc6 is a multi-subunit complex with a poorly understood function in DNA replication and repair. One of its subunits, Nse2, is able to promote the addition of a small ubiquitin-like protein modifier (SUMO) to specific target proteins. Recent work has revealed that the Smc5-Smc6 complex is required for the progression of replication forks through damaged DNA and is recruited de novo to forks that undergo collapse. In addition, Smc5-Smc6 mediate repair of DNA breaks by homologous recombination between sister-chromatids. Thus, Smc5-Smc6 is anticipated to promote recombinational repair at stalled/collapsed replication forks. My laboratory proposes to develop molecular techniques to study replication at the level of single replication forks. We will employ these assays to identify and dissect the function of factors involved in replication fork stability and repair. We will place an emphasis on the study of the Smc5-Smc6 complex in these processes because of its potential roles in recombination-dependent fork repair and restart. We also propose to identify novel Nse2 substrates involved in DNA repair using yeast model systems. Specifically, we will address the following points: (1) Development of assays for analysis of factors involved in stabilisation, collapse and re-start of single-forks, (2) Analysis of the roles of Smc5-Smc6 in fork biology using developed techniques, (3) Isolation and functional analysis of novel Nse2 substrates.
Summary
DNA replication represents a dangerous moment in the life of the cell as endogenous and exogenous events challenge genome integrity by interfering with the progression, stability and restart of the replication fork. Failure to protect stalled forks or to process the replication fork appropriately contribute to the pathological mechanisms giving rise to cancer, therefore an understanding of the intricate mechanisms that ensure fork integrity can provide targets for new chemotherapeutic assays. Smc5-Smc6 is a multi-subunit complex with a poorly understood function in DNA replication and repair. One of its subunits, Nse2, is able to promote the addition of a small ubiquitin-like protein modifier (SUMO) to specific target proteins. Recent work has revealed that the Smc5-Smc6 complex is required for the progression of replication forks through damaged DNA and is recruited de novo to forks that undergo collapse. In addition, Smc5-Smc6 mediate repair of DNA breaks by homologous recombination between sister-chromatids. Thus, Smc5-Smc6 is anticipated to promote recombinational repair at stalled/collapsed replication forks. My laboratory proposes to develop molecular techniques to study replication at the level of single replication forks. We will employ these assays to identify and dissect the function of factors involved in replication fork stability and repair. We will place an emphasis on the study of the Smc5-Smc6 complex in these processes because of its potential roles in recombination-dependent fork repair and restart. We also propose to identify novel Nse2 substrates involved in DNA repair using yeast model systems. Specifically, we will address the following points: (1) Development of assays for analysis of factors involved in stabilisation, collapse and re-start of single-forks, (2) Analysis of the roles of Smc5-Smc6 in fork biology using developed techniques, (3) Isolation and functional analysis of novel Nse2 substrates.
Max ERC Funding
893 396 €
Duration
Start date: 2008-09-01, End date: 2013-08-31
Project acronym CISGLA
Project Architecture and Asceticism: Cultural Interaction between Syria and Georgia in Late Antiquity
Researcher (PI) Emma Loosley
Host Institution (HI) THE UNIVERSITY OF EXETER
Call Details Starting Grant (StG), SH5, ERC-2012-StG_20111124
Summary "The proposed research is intended to initiate the process of formulating an integrated approach to the evolution and spread of early Christianity in the Eastern Mediterranean, Caucasus and Middle East. Thus far this work has been constrained by geographical, linguistic and denominational boundaries meaning that there has been a plethora of regional studies in the field but no comprehensive overview attempting to develop a coherent picture of wider cultural interaction. By beginning a project that seeks to explore the relationship between the Syrian and Georgian Churches from a variety of different disciplines, this project intends to develop a framework from which to construct a comprehensive overview of the development of Eastern Christianity in late antiquity.
This work will open a new phase in the study of late antique Christianity by seeking to place the different denominations that split apart after the Christological and Mariological controversies of the fifth century into a wider context that allows comparative study of their liturgical, architectural and theological development and interaction. It is logical to begin with the Syrian and Georgian traditions as the Georgians wrote in an Aramaic script, known as Armazi, until the evolution of the Georgian alphabet in the fifth century. Syriac, the liturgical language of the Syrian Church tradition, is also an Aramaic dialect that developed in the city of Edessa (now Şanliurfa in south-eastern Turkey). Edessa stood between Syria and Georgia and provided the main conduit for the transmission of culture between the two regions. In addition Georgia historically received monasticism and a renewed evangelical movement through the ""Thirteen Syrian Fathers"", thirteen Syrian monks who were credited with expanding on the work of evangelisation begun in Georgia by St Nino of Cappadocia in the fourth century. Beginning with these two inter-linked traditions this framework can be applied to other traditions in future."
Summary
"The proposed research is intended to initiate the process of formulating an integrated approach to the evolution and spread of early Christianity in the Eastern Mediterranean, Caucasus and Middle East. Thus far this work has been constrained by geographical, linguistic and denominational boundaries meaning that there has been a plethora of regional studies in the field but no comprehensive overview attempting to develop a coherent picture of wider cultural interaction. By beginning a project that seeks to explore the relationship between the Syrian and Georgian Churches from a variety of different disciplines, this project intends to develop a framework from which to construct a comprehensive overview of the development of Eastern Christianity in late antiquity.
This work will open a new phase in the study of late antique Christianity by seeking to place the different denominations that split apart after the Christological and Mariological controversies of the fifth century into a wider context that allows comparative study of their liturgical, architectural and theological development and interaction. It is logical to begin with the Syrian and Georgian traditions as the Georgians wrote in an Aramaic script, known as Armazi, until the evolution of the Georgian alphabet in the fifth century. Syriac, the liturgical language of the Syrian Church tradition, is also an Aramaic dialect that developed in the city of Edessa (now Şanliurfa in south-eastern Turkey). Edessa stood between Syria and Georgia and provided the main conduit for the transmission of culture between the two regions. In addition Georgia historically received monasticism and a renewed evangelical movement through the ""Thirteen Syrian Fathers"", thirteen Syrian monks who were credited with expanding on the work of evangelisation begun in Georgia by St Nino of Cappadocia in the fourth century. Beginning with these two inter-linked traditions this framework can be applied to other traditions in future."
Max ERC Funding
954 523 €
Duration
Start date: 2012-11-01, End date: 2017-10-31