Project acronym CHROMATINREPLICATION
Project How to Replicate Chromatin - Maturation, Timing Control and Stress-Induced Aberrations
Researcher (PI) Anja Groth
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Starting Grant (StG), LS1, ERC-2011-StG_20101109
Summary Inheritance of DNA sequence and its proper organization into chromatin is fundamental for eukaryotic life. The challenge of propagating genetic and epigenetic information is met in S phase and entails genome-wide disruption and restoration of chromatin coupled to faithful copying of DNA. How specific chromatin structures are restored on new DNA and transmitted through mitotic cell division remains a fundamental question in biology central to understand cell fate and identity.
Chromatin restoration on new DNA involves a complex set of events including nucleosome assembly and remodelling, restoration of marks on DNA and histones, deposition of histone variants and establishment of higher order chromosomal structures including sister-chromatid cohesion. To dissect these fundamental processes and their coordination in time and space with DNA replication, we have developed a novel technology termed nascent chromatin capture (NCC) that provides unique possibility for biochemical and proteomic analysis of chromatin replication in human cells. I propose to apply this innovative cutting-edge technique for a comprehensive characterization of chromatin restoration during DNA replication and to reveal how replication timing and genotoxic stress impact on final chromatin state. This highly topical project brings together the fields of chromatin biology, DNA replication, epigenetics and genome stability and we expect to make groundbreaking discoveries that will improve our understanding of human development, somatic cell reprogramming and complex diseases like cancer.
The proposed research will 1) identify and characterize novel mechanisms in chromatin restoration and 2) address molecularly how replication timing and genotoxic insults influence chromatin maturation and final chromatin state.
Summary
Inheritance of DNA sequence and its proper organization into chromatin is fundamental for eukaryotic life. The challenge of propagating genetic and epigenetic information is met in S phase and entails genome-wide disruption and restoration of chromatin coupled to faithful copying of DNA. How specific chromatin structures are restored on new DNA and transmitted through mitotic cell division remains a fundamental question in biology central to understand cell fate and identity.
Chromatin restoration on new DNA involves a complex set of events including nucleosome assembly and remodelling, restoration of marks on DNA and histones, deposition of histone variants and establishment of higher order chromosomal structures including sister-chromatid cohesion. To dissect these fundamental processes and their coordination in time and space with DNA replication, we have developed a novel technology termed nascent chromatin capture (NCC) that provides unique possibility for biochemical and proteomic analysis of chromatin replication in human cells. I propose to apply this innovative cutting-edge technique for a comprehensive characterization of chromatin restoration during DNA replication and to reveal how replication timing and genotoxic stress impact on final chromatin state. This highly topical project brings together the fields of chromatin biology, DNA replication, epigenetics and genome stability and we expect to make groundbreaking discoveries that will improve our understanding of human development, somatic cell reprogramming and complex diseases like cancer.
The proposed research will 1) identify and characterize novel mechanisms in chromatin restoration and 2) address molecularly how replication timing and genotoxic insults influence chromatin maturation and final chromatin state.
Max ERC Funding
1 692 737 €
Duration
Start date: 2011-11-01, End date: 2017-04-30
Project acronym ECOGENOMICINBREEDING
Project Comparative studies of inbreeding effects on evolutionary processes in non-model animal populations
Researcher (PI) Trine Bilde
Host Institution (HI) AARHUS UNIVERSITET
Call Details Starting Grant (StG), LS8, ERC-2011-StG_20101109
Summary Comparative studies of inbreeding and evolution in non-model animal populations: a research proposal directed towards integrating ecological and evolutionary research on inbreeding. Specifically, my aim is to apply novel ecogenomics tools in the study of evolutionary consequences of inbreeding in non-model animal populations. At present, our understanding of inbreeding is dominated by studies of a small number of model organisms. I will undertake comparative studies on inbreeding effects in a genus of spiders containing independently evolved naturally inbreeding species as well as outcrossing sister species. The study of a naturally inbreeding animal species will provide unique insights to consequences of inbreeding for population genetic structure, genome-wide genetic diversity, and evolution of life history traits. Social spiders are not only unique because they naturally inbreed, but also by being cooperative and showing allomaternal brood care including self-sacrifice, and they evolve highly female-biased sex-ratios, a trait that is not well understood in diploid species. My research objectives are 1) to establish a robust phylogeny for comparative studies; 2) to quantify the effects of inbreeding on the genetic diversity within and between populations; 3) to estimate gene flow among inbred lineages to determine whether inbred lineages diversify but retain the potential for gene exchange, or undergo cryptic speciation; 4) to determine effects of inbreeding on gene expression; 5) to investigate the mechanism underlying the genetic sex determination system that cause female biased sex-ratios; and finally 6) to determine whether sex-ratio is under adaptive parental control in response to genetic relatedness and ecological constraints. Addressing these objectives will generate novel insights and expand current knowledge on the evolutionary ecology of inbreeding in wild animal populations.
Summary
Comparative studies of inbreeding and evolution in non-model animal populations: a research proposal directed towards integrating ecological and evolutionary research on inbreeding. Specifically, my aim is to apply novel ecogenomics tools in the study of evolutionary consequences of inbreeding in non-model animal populations. At present, our understanding of inbreeding is dominated by studies of a small number of model organisms. I will undertake comparative studies on inbreeding effects in a genus of spiders containing independently evolved naturally inbreeding species as well as outcrossing sister species. The study of a naturally inbreeding animal species will provide unique insights to consequences of inbreeding for population genetic structure, genome-wide genetic diversity, and evolution of life history traits. Social spiders are not only unique because they naturally inbreed, but also by being cooperative and showing allomaternal brood care including self-sacrifice, and they evolve highly female-biased sex-ratios, a trait that is not well understood in diploid species. My research objectives are 1) to establish a robust phylogeny for comparative studies; 2) to quantify the effects of inbreeding on the genetic diversity within and between populations; 3) to estimate gene flow among inbred lineages to determine whether inbred lineages diversify but retain the potential for gene exchange, or undergo cryptic speciation; 4) to determine effects of inbreeding on gene expression; 5) to investigate the mechanism underlying the genetic sex determination system that cause female biased sex-ratios; and finally 6) to determine whether sex-ratio is under adaptive parental control in response to genetic relatedness and ecological constraints. Addressing these objectives will generate novel insights and expand current knowledge on the evolutionary ecology of inbreeding in wild animal populations.
Max ERC Funding
1 497 248 €
Duration
Start date: 2012-01-01, End date: 2017-09-30
Project acronym NERCOMP
Project Structural studies of Nucleotide Excision Repair complexes
Researcher (PI) Marcin Nowotny
Host Institution (HI) INTERNATIONAL INSTITUTE OF MOLECULAR AND CELL BIOLOGY
Call Details Starting Grant (StG), LS1, ERC-2011-StG_20101109
Summary "DNA damage caused by chemical and physical factors can lead to detrimental effects to the cell and must be corrected. One of the primary pathways to achieve this repair is nucleotide excision repair (NER). In NER, the DNA damage is first located, a stretch of bases harboring the lesion is removed, and the gap is filled by a DNA polymerase. The unique feature of NER is its ability to correct a wide spectrum of DNA modifications of different sizes and chemical structures.
The aim of the project is to structurally and biochemically characterize protein complexes involved in NER pathways in bacteria and eukaryotes.
In bacterial NER, a complex of UvrA and UvrB proteins locates the damage and verifies its presence. In the first part of the project we plan to determine the crystal and small-angle X-ray scattering (SAXS) structures of a UvrA-UvrB-DNA complex to elucidate the details of the mechanism of the first steps of bacterial NER.
In eukaryotic NER, the 3′ incision is executed by XPG/Rad2 protein. Currently, no structural information is available for this protein. In the second part of the project, we plan to solve the crystal structures of XPG/Rad2 nuclease in apo form and in complex with the DNA substrate to elucidate the mechanism of the 3′ cut. We also plan to determine the structure of XPG/Rad2 in complex with the XPG/Rad2-binding domain from the p62 component of TFIIH, which will be an important building block for the determination of the architecture of the eukaryotic NER pre-incision complex.
The third part of the project will elucidate the structure and mechanism of the Rad16-Rad7 yeast NER complex. It is implicated in numerous stages of NER, from damage detection to ubiquitination of other NER components. We plan to solve the crystal structures of the Rad16-Rad7 alone and in complexes with DNA or partner protein Abf1 to elucidate the mechanisms of various activities of Rad16-Rad7 and help design experiments that could test the in vivo function of this complex."
Summary
"DNA damage caused by chemical and physical factors can lead to detrimental effects to the cell and must be corrected. One of the primary pathways to achieve this repair is nucleotide excision repair (NER). In NER, the DNA damage is first located, a stretch of bases harboring the lesion is removed, and the gap is filled by a DNA polymerase. The unique feature of NER is its ability to correct a wide spectrum of DNA modifications of different sizes and chemical structures.
The aim of the project is to structurally and biochemically characterize protein complexes involved in NER pathways in bacteria and eukaryotes.
In bacterial NER, a complex of UvrA and UvrB proteins locates the damage and verifies its presence. In the first part of the project we plan to determine the crystal and small-angle X-ray scattering (SAXS) structures of a UvrA-UvrB-DNA complex to elucidate the details of the mechanism of the first steps of bacterial NER.
In eukaryotic NER, the 3′ incision is executed by XPG/Rad2 protein. Currently, no structural information is available for this protein. In the second part of the project, we plan to solve the crystal structures of XPG/Rad2 nuclease in apo form and in complex with the DNA substrate to elucidate the mechanism of the 3′ cut. We also plan to determine the structure of XPG/Rad2 in complex with the XPG/Rad2-binding domain from the p62 component of TFIIH, which will be an important building block for the determination of the architecture of the eukaryotic NER pre-incision complex.
The third part of the project will elucidate the structure and mechanism of the Rad16-Rad7 yeast NER complex. It is implicated in numerous stages of NER, from damage detection to ubiquitination of other NER components. We plan to solve the crystal structures of the Rad16-Rad7 alone and in complexes with DNA or partner protein Abf1 to elucidate the mechanisms of various activities of Rad16-Rad7 and help design experiments that could test the in vivo function of this complex."
Max ERC Funding
1 498 000 €
Duration
Start date: 2012-01-01, End date: 2017-12-31
