A5028277342- DNA Repair Mechanisms
- CRISPR and Genetic Engineering
- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- Fungal and yeast genetics research
- Chromosomal and Genetic Variations
- Telomeres, Telomerase, and Senescence
- DNA and Nucleic Acid Chemistry
- RNA modifications and cancer
- Photosynthetic Processes and Mechanisms
- Microtubule and mitosis dynamics
- Carcinogens and Genotoxicity Assessment
- PARP inhibition in cancer therapy
- Real-time simulation and control systems
- Erythrocyte Function and Pathophysiology
- Bacterial Genetics and Biotechnology
- Nanopore and Nanochannel Transport Studies
- Mitochondrial Function and Pathology
- Muscle Physiology and Disorders
- Epigenetics and DNA Methylation
- Polyomavirus and related diseases
- RNA regulation and disease
- Nuclear Structure and Function
- RNA Interference and Gene Delivery
- Cancer-related molecular mechanisms research
Imperial College London
2020-2025
MRC London Institute of Medical Sciences
2021-2025
Università della Svizzera italiana
2017-2022
ETH Zurich
2019-2020
Medical Research Council
2020
University of Zurich
2014-2020
Bristol Institute for Transfusion Sciences
2016
NHS Blood and Transplant
2016
MutLγ, a heterodimer of the MutL homologues Mlh1 and Mlh3, plays critical role during meiotic homologous recombination. The function Mlh3 is fully dependent on integrity putative nuclease motif DQHAX2EX4E, inferring that anticipated activity Mlh1-Mlh3 involved in processing joint molecules to generate crossover recombination products. Although vast body genetic cell biological data regarding available, mechanistic insights into its have been lacking due unavailability recombinant protein...
Meiotic crossover formation requires the stabilization of early recombination intermediates by a set proteins and occurs within environment chromosome axis, structure important for regulation meiotic events. The molecular mechanisms underlying connecting axis localization are elusive. Here, we identified ZZS (Zip2–Zip4–Spo16) complex, required formation, which carries two distinct activities: one provided Zip4, acts as hub through physical interactions with components machinery, other...
Abstract Human DNA licensing initiates replication fork assembly and replication. This reaction promotes the loading of hMCM2-7 complex on DNA, which represents core replicative helicase that unwinds during S-phase. Here, we report reconstitution human using purified proteins. We showed in vitro is specific results high-salt resistant double-hexamers. With ATPγS, an hORC1-5-hCDC6-hCDT1-hMCM2-7 (hOCCM) assembles independent hORC6, but hORC6 enhances double-hexamer formation. determined hOCCM...
Gene conversions resulting from meiotic recombination are critical in shaping genome diversification and evolution. How the extent of gene is regulated unknown. Here we show that budding yeast mismatch repair related MutLβ complex, Mlh1-Mlh2, specifically interacts with conserved Mer3 helicase, which recruits it to hotspots, independently recognition. This recruitment essential limit conversion tract lengths genome-wide, without affecting crossover formation. Contrary expectations, helicase...
Abstract SMARCAL1, ZRANB3 and HLTF are required for the remodeling of replication forks upon stress to promote genome stability. RAD51, along with RAD51 paralog complex, were also found have recombination-independent functions in fork reversal, yet underlying mechanisms remained unclear. Using reconstituted reactions, we build previous data show that unequal biochemical capacities, explaining why they non-redundant functions. SMARCAL1 uniquely anneals RPA-coated ssDNA, which depends on its...
Crossovers generated during the repair of programmed meiotic double-strand breaks must be tightly regulated to promote accurate homolog segregation without deleterious outcomes, such as aneuploidy. The Mlh1-Mlh3 (MutLγ) endonuclease complex is critical for crossover resolution, which involves mechanistically unclear interplay between MutLγ and Exo1 polo kinase Cdc5. Using budding yeast gain temporal genetic traction on regulation, we find that constitutively interacts with Exo1. Upon...
Significance During meiosis, programmed chromosome breakage and subsequent double-stranded DNA (dsDNA) break repair help ensure correct segregation promote genetic diversity of the progeny. In budding yeast, which utilizes meiotic recombination pathways conserved in mice humans, majority crossovers are initiated through formation a Holliday junction, requires endonuclease activity Mlh1-Mlh3 mismatch factor to be resolved exclusively into crossover product. Here, we combined structural...
Summary During prophase of the first meiotic division, cells deliberately break their DNA. These DNA breaks are repaired by homologous recombination, which facilitates proper chromosome segregation and enables reciprocal exchange segments between chromosomes, thus promoting genetic diversity in progeny 1 . A successful completion recombination requires nucleolytic processing intermediates. Genetic cellular data implicated a pathway dependent on putative MLH1-MLH3 (MutLγ) nuclease generating...
Meiotic recombination ensures proper chromosome segregation to form viable gametes and results in gene conversions events between homologs. Conversion tracts are shorter meiosis than mitotically dividing cells. This at least part from the binding of a complex, containing Mer3 helicase MutLβ heterodimer, meiotic intermediates. The molecular actors inhibited by this complex elusive. Pif1 DNA is known stimulate polymerase delta (Pol δ) -mediated synthesis D-loops, allowing long required for...
SUMMARY Human DNA licensing initiates the process of replication fork assembly. Specifically, this reaction leads to loading hMCM2-7 on DNA, which represents core replicative helicase that unwinds during S-phase. Here, we report biochemical reconstitution human using purified proteins, structural and functional analysis reveal impact cancer-associated mutations licensing. We showed in vitro is specific results assembly high-salt resistant double-hexamers, final product used ATPγS block...
Abstract Dna2 is an essential nuclease-helicase that acts in several distinct DNA metabolic pathways including replication and recombination. To balance these functions prevent unscheduled degradation, activities must be regulated. Here we show Saccharomyces cerevisiae function controlled by sumoylation. We map the sumoylation sites to N-terminal regulatory domain of vitro recombinant impairs its nuclease but not helicase activity. In cells, total levels non-sumoylatable variant are...
Background Bone marrow examination has been the confirmatory test for congenital dyserythropoietic anemia type II (CDAII). Occasional spherocytes on peripheral blood smear can confound diagnosis. Since a screening is still unavailable, we explored feasibility of using flow cytometry as preliminary method. Methods Thirteen monoclonal antibodies with specificities eight erythrocyte membrane proteins were used in FACS analysis to probe cellular features red cells from CDAII, normal adults,...
Abstract Crossovers generated during the repair of programmed double-strand breaks (DSBs) homologous recombination are essential for fertility to allow accurate homolog segregation first meiotic division. Most crossovers arise through cleavage intermediates by Mlh1-Mlh3 (MutLγ) endonuclease and an elusive non-catalytic function Exo1, require Polo kinase Cdc5. Here we show in budding yeast that MutLγ forms a constitutive complex with cells transiently contacts Msh4-Msh5 (MutSγ) heterodimer,...