Frank Uhlmann | |
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 Frank Uhlmann in 2015, portrait via the Royal Society | |
| Alma mater | University of Tübingen (PhD) |
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| Thesis | Reconstitution and characterisation of human replication factor C (1997) |
| Website | crick |
Frank Uhlmann FRS [1] is a group leader at the Francis Crick Institute in London. [6] [7] [8] [9] [10] [11] [12]
Uhlmann was educated at the University of Tübingen where he was awarded a PhD in 1997. [4] [13] During his PhD, he worked with Jerard Hurwitz at the Memorial Sloan Kettering Cancer Center in New York City. [14] [15] [16]
Following his PhD, Uhlmann moved to the Research Institute of Molecular Pathology in Vienna for postdoctoral research with Kim Nasmyth. In 2000, he established a laboratory at the Imperial Cancer Research Fund (now Cancer Research UK) [17] in London, which ultimately became part of the Francis Crick Institute. [16]
Uhlmann was elected a Fellow of the Royal Society (FRS) in 2015. His certificate of election reads:
Frank Uhlmann's discovery with Nasmyth of 'separase', the protease that cleaves the cohesive links between sister chromatids to trigger anaphase is a key contribution to our understanding of the cell cycle. He has made major contributions to our understanding of the mechanisms of sister chromatid cohesion, and their relationship to cell cycle regulation. He generated the first chromosome-wide high resolution maps of proteins involved in chromosome packaging and segregation. He showed that yeast cohesins accumulate at sites of converging transcription distinct from the sites where their loading factors bind, apparently reflecting interaction with the transcription apparatus; and that cohesin loading factors are recruited to specific chromosomal sites through interaction with the nucleosome remodelling complex Rsc. He has identified genes required for cohesion establishment, and shown that one of these, EcoI, acetylates cohesin during DNA replication, thereby locking it onto DNA and his studies of the link between cohesion regulation and the cell cycle have shown that as well as cleaving cohesin, separase promotes mitotic exit by activating the Cdc14 phosphatase in a protease-independent manner. [1]
In 2006, Uhlmann was also elected a member of the European Molecular Biology Organization (EMBO) [2] and awarded the EMBO Gold Medal. [5] [3]
Anaphase is the stage of mitosis after the process of metaphase, when replicated chromosomes are split and the newly-copied chromosomes are moved to opposite poles of the cell. Chromosomes also reach their overall maximum condensation in late anaphase, to help chromosome segregation and the re-formation of the nucleus.
Nondisjunction is the failure of homologous chromosomes or sister chromatids to separate properly during cell division (mitosis/meiosis). There are three forms of nondisjunction: failure of a pair of homologous chromosomes to separate in meiosis I, failure of sister chromatids to separate during meiosis II, and failure of sister chromatids to separate during mitosis. Nondisjunction results in daughter cells with abnormal chromosome numbers (aneuploidy).
Anaphase-promoting complex is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. The APC/C is a large complex of 11–13 subunit proteins, including a cullin (Apc2) and RING (Apc11) subunit much like SCF. Other parts of the APC/C have unknown functions but are highly conserved.
The spindle checkpoint, also known as the metaphase-to-anaphase transition, the spindle assembly checkpoint (SAC), the metaphase checkpoint, or the mitotic checkpoint, is a cell cycle checkpoint during metaphase of mitosis or meiosis that prevents the separation of the duplicated chromosomes (anaphase) until each chromosome is properly attached to the spindle. To achieve proper segregation, the two kinetochores on the sister chromatids must be attached to opposite spindle poles. Only this pattern of attachment will ensure that each daughter cell receives one copy of the chromosome. The defining biochemical feature of this checkpoint is the stimulation of the anaphase-promoting complex by M-phase cyclin-CDK complexes, which in turn causes the proteolytic destruction of cyclins and proteins that hold the sister chromatids together.
A kinetochore is a disc-shaped protein structure associated with duplicated chromatids in eukaryotic cells where the spindle fibers attach during cell division to pull sister chromatids apart. The kinetochore assembles on the centromere and links the chromosome to microtubule polymers from the mitotic spindle during mitosis and meiosis. The term kinetochore was first used in a footnote in a 1934 Cytology book by Lester W. Sharp and commonly accepted in 1936. Sharp's footnote reads: "The convenient term kinetochore has been suggested to the author by J. A. Moore", likely referring to John Alexander Moore who had joined Columbia University as a freshman in 1932.
Kim Ashley Nasmyth is an English geneticist, the Whitley Professor of Biochemistry at the University of Oxford, a Fellow of Trinity College, Oxford, former scientific director of the Research Institute of Molecular Pathology (IMP), and former head of the Department of Biochemistry, University of Oxford. He is best known for his work on the segregation of chromosomes during cell division.
Separase, also known as separin, is a cysteine protease responsible for triggering anaphase by hydrolysing cohesin, which is the protein responsible for binding sister chromatids during the early stage of anaphase. In humans, separin is encoded by the ESPL1 gene.
Securin is a protein involved in control of the metaphase-anaphase transition and anaphase onset. Following bi-orientation of chromosome pairs and inactivation of the spindle checkpoint system, the underlying regulatory system, which includes securin, produces an abrupt stimulus that induces highly synchronous chromosome separation in anaphase.
SMC complexes represent a large family of ATPases that participate in many aspects of higher-order chromosome organization and dynamics. SMC stands for Structural Maintenance of Chromosomes.
Cohesin is a protein complex that mediates sister chromatid cohesion, homologous recombination, and DNA looping. Cohesin is formed of SMC3, SMC1, SCC1 and SCC3. Cohesin holds sister chromatids together after DNA replication until anaphase when removal of cohesin leads to separation of sister chromatids. The complex forms a ring-like structure and it is believed that sister chromatids are held together by entrapment inside the cohesin ring. Cohesin is a member of the SMC family of protein complexes which includes Condensin, MukBEF and SMC-ScpAB.
Mad2 is an essential spindle checkpoint protein. The spindle checkpoint system is a regulatory system that restrains progression through the metaphase-to-anaphase transition. The Mad2 gene was first identified in the yeast S. cerevisiae in a screen for genes which when mutated would confer sensitivity to microtubule poisons. The human orthologues of Mad2 were first cloned in a search for human cDNAs that would rescue the microtubule poison-sensitivity of a yeast strain in which a kinetochore binding protein was missing. The protein was shown to be present at unattached kinetochores and antibody inhibition studies demonstrated it was essential to execute a block in the metaphase-to-anaphase transition in response to the microtubule poison nocodazole. Subsequent cloning of the Xenopus laevis orthologue, facilitated by the sharing of the human sequence, allowed for the characterization of the mitotic checkpoint in egg extracts.
Chromosome segregation is the process in eukaryotes by which two sister chromatids formed as a consequence of DNA replication, or paired homologous chromosomes, separate from each other and migrate to opposite poles of the nucleus. This segregation process occurs during both mitosis and meiosis. Chromosome segregation also occurs in prokaryotes. However, in contrast to eukaryotic chromosome segregation, replication and segregation are not temporally separated. Instead segregation occurs progressively following replication.
Double-strand-break repair protein rad21 homolog is a protein that in humans is encoded by the RAD21 gene. RAD21, an essential gene, encodes a DNA double-strand break (DSB) repair protein that is evolutionarily conserved in all eukaryotes from budding yeast to humans. RAD21 protein is a structural component of the highly conserved cohesin complex consisting of RAD21, SMC1A, SMC3, and SCC3 [ STAG1 (SA1) and STAG2 (SA2) in multicellular organisms] proteins, involved in sister chromatid cohesion.
Replication factor C subunit 2 is a protein that in humans is encoded by the RFC2 gene.
Structural maintenance of chromosomes protein 3 (SMC3) is a protein that in humans is encoded by the SMC3 gene. SMC3 is a subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. Cohesin is formed of SMC3, SMC1, RAD21 and either SA1 or SA2. In humans, SMC3 is present in all cohesin complexes whereas there are multiple paralogs for the other subunits.
Wings apart-like protein homolog (WAPL) is a protein that in humans is encoded by the WAPAL gene. WAPL is a key regulator of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. Cohesin is formed of SMC3, SMC1, RAD21 and either SA1 or SA2. Cohesin has a ring-like arrangement and it is thought that it associates with the chromosome by entrapping it whether as a loop of DNA, a single strand or a pair of sister chromosomes. WAPL forms a complex with PDS5A or PDS5B and releases cohesin from DNA by opening the interface between SMC3 and RAD21.
Meiotic recombination protein REC8 homolog is a protein that in humans is encoded by the REC8 gene.
A series of biochemical switches control transitions between and within the various phases of the cell cycle. The cell cycle is a series of complex, ordered, sequential events that control how a single cell divides into two cells, and involves several different phases. The phases include the G1 and G2 phases, DNA replication or S phase, and the actual process of cell division, mitosis or M phase. During the M phase, the chromosomes separate and cytokinesis occurs.
Sister chromatid cohesion refers to the process by which sister chromatids are paired and held together during certain phases of the cell cycle. Establishment of sister chromatid cohesion is the process by which chromatin-associated cohesin protein becomes competent to physically bind together the sister chromatids. In general, cohesion is established during S phase as DNA is replicated, and is lost when chromosomes segregate during mitosis and meiosis. Some studies have suggested that cohesion aids in aligning the kinetochores during mitosis by forcing the kinetochores to face opposite cell poles.
Structural maintenance of chromosomes protein 1B (SMC-1B) is a protein that in humans is encoded by the SMC1B gene. SMC proteins engage in chromosome organization and can be broken into 3 groups based on function which are cohesins, condensins, and DNA repair. SMC-1B belongs to a family of proteins required for chromatid cohesion and DNA recombination during meiosis and mitosis. SMC1ß protein appears to participate with other cohesins REC8, STAG3 and SMC3 in sister-chromatid cohesion throughout the whole meiotic process in human oocytes.
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