Papers by Camilla Colding
Regulation of Replication Recovery and Genome Integrity:Cdc48-Mediated Turnover of Mrc1 and Cmr1 in INQ
Cell Host & Microbe Resource Dynamics and Stabilization of the Human Gut Microbiome during the First Year of Life
DNA replication stress is a source of genome instability and a replication checkpoint has evolved... more DNA replication stress is a source of genome instability and a replication checkpoint has evolved to enable fork stabilisation and completion of replication during stress. Mediator of the replication checkpoint 1 (Mrc1) is the primary mediator of this response in Saccharomyces cerevisiae. Mrc1 is partially sequestered in the intranuclear quality control compartment (INQ) upon methyl methanesulfonate (MMS)-induced replication stress. Here we show that Mrc1 re-localizes from the replication fork to INQ during replication stress. Sequestration of Mrc1 in INQ is facilitated by the Btn2 chaperone and the Cdc48 segregase is required to release Mrc1 from INQ during recovery from replication stress. Consistently, we show that Cdc48 colocalizes with Mrc1 in INQ and we find that Mrc1 is recognized by the Cdc48 cofactors Ufd1 and Otu1, which contribute to clearance of Mrc1 from INQ. Our findings suggest that INQ localization of Mrc1 and Cdc48 function to facilitate replication stress recovery ...
Nature Communications, 2020
Ethanol is a ubiquitous environmental stressor that is toxic to all lifeforms. Here, we use the m... more Ethanol is a ubiquitous environmental stressor that is toxic to all lifeforms. Here, we use the model eukaryote Saccharomyces cerevisiae to show that exposure to sublethal ethanol concentrations causes DNA replication stress and an increased mutation rate. Specifically, we find that ethanol slows down replication and affects localization of Mrc1, a conserved protein that helps stabilize the replisome. In addition, ethanol exposure also results in the recruitment of error-prone DNA polymerases to the replication fork. Interestingly, preventing this recruitment through mutagenesis of the PCNA/Pol30 polymerase clamp or deleting specific error-prone polymerases abolishes the mutagenic effect of ethanol. Taken together, this suggests that the mutagenic effect depends on a complex mechanism, where dysfunctional replication forks lead to recruitment of error-prone polymerases. Apart from providing a general mechanistic framework for the mutagenic effect of ethanol, our findings may also pr...
Nature Biotechnology, 2019
Are Postoperative Restrictions of Movements After Total Hip Replacement Necessary? A Prospective Randomized Study of 80 Total Hip Replacements
Journal of Bone Joint Surgery British Volume, Sep 1, 2012
Introduction The postoperative management of patients after total hip replacement traditionally i... more Introduction The postoperative management of patients after total hip replacement traditionally includes restrictions of movements and the use of aids (toiletelevation, sleeping pillow, a.o.) in the first 3 months after operation. Few studies have investigated the benefit of such restrictions. The aim of the present study was to evaluate how patients with total hip replacements (THR) are doing with and without restrictions in the first 3 months after surgery, and if walking ability and patients satisfaction was influenced by the postoperative regime. Patients and Methods 80 patients undergoing primary uncemented THR were randomized to either the conventional regime with restrictions of movement and obligatory use of aids, or a postoperative regime without restrictions. Surgery was performed through a posterolateral short incision. The femoral component was the uncemented Bimetric prosthesis, non collared with HA coating, and a 36 mm femoral head. The cup was the Trilogy cup with a highly crosslinked polyethylen liner. No postoperative drainage was used and immediate weight bearing was allowed in both groups. We monitored walking speed, TUG score (timed up and go) and VAS pain score. The patients were scored by a trained physiotherapist preoperatively, 2 times each day during admission, and 14 and 90 days after surgery. Radiographic examination was performed after 3 days and after 3 months. At the 3 months evaluation a SF-36 score was registered. Results The two groups were similar in age, operation time blood loss, and position of the prosthesis. None of the patients had postoperative dislocation. No significant difference was seen in any of the registered parameters (p Conclusion There is no significant difference in TUG test, 10m test, SF 36 score and VAS score the first 3 months after THR in the 2 groups. We did not see an increase in postoperative complications, which implies that postoperative mobilisation without restrictions, can be allowed without the risk of increased complications, and the use of aids in activities of daily living are not necessary. This also implies the possibility of savings in the rehabilitation of patients after THR.
Nature biotechnology, Jan 28, 2015
We established a catalog of the mouse gut metagenome comprising ∼2.6 million nonredundant genes b... more We established a catalog of the mouse gut metagenome comprising ∼2.6 million nonredundant genes by sequencing DNA from fecal samples of 184 mice. To secure high microbiome diversity, we used mouse strains of diverse genetic backgrounds, from different providers, kept in different housing laboratories and fed either a low-fat or high-fat diet. Similar to the human gut microbiome, >99% of the cataloged genes are bacterial. We identified 541 metagenomic species and defined a core set of 26 metagenomic species found in 95% of the mice. The mouse gut microbiome is functionally similar to its human counterpart, with 95.2% of its Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologous groups in common. However, only 4.0% of the mouse gut microbial genes were shared (95% identity, 90% coverage) with those of the human gut microbiome. This catalog provides a useful reference for future studies.
Cell host & microbe, Jan 13, 2015
The gut microbiota is central to human health, but its establishment in early life has not been q... more The gut microbiota is central to human health, but its establishment in early life has not been quantitatively and functionally examined. Applying metagenomic analysis on fecal samples from a large cohort of Swedish infants and their mothers, we characterized the gut microbiome during the first year of life and assessed the impact of mode of delivery and feeding on its establishment. In contrast to vaginally delivered infants, the gut microbiota of infants delivered by C-section showed significantly less resemblance to their mothers. Nutrition had a major impact on early microbiota composition and function, with cessation of breast-feeding, rather than introduction of solid food, being required for maturation into an adult-like microbiota. Microbiota composition and ecological network had distinctive features at each sampled stage, in accordance with functional maturation of the microbiome. Our findings establish a framework for understanding the interplay between the gut microbiome...
Nature communications, Jan 30, 2015
DNA replication stress is a source of genomic instability. Here we identify changed mutation rate... more DNA replication stress is a source of genomic instability. Here we identify changed mutation rate 1 (Cmr1) as a factor involved in the response to DNA replication stress in Saccharomyces cerevisiae and show that Cmr1-together with Mrc1/Claspin, Pph3, the chaperonin containing TCP1 (CCT) and 25 other proteins-define a novel intranuclear quality control compartment (INQ) that sequesters misfolded, ubiquitylated and sumoylated proteins in response to genotoxic stress. The diversity of proteins that localize to INQ indicates that other biological processes such as cell cycle progression, chromatin and mitotic spindle organization may also be regulated through INQ. Similar to Cmr1, its human orthologue WDR76 responds to proteasome inhibition and DNA damage by relocalizing to nuclear foci and physically associating with CCT, suggesting an evolutionarily conserved biological function. We propose that Cmr1/WDR76 plays a role in the recovery from genotoxic stress through regulation of the tu...
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Papers by Camilla Colding