Dr. Weeks’ Comment: Saccharomyces cerevisiae has long been known to stimulate cancer cell death (apoptosis) but recently we note a new anti-cancer property been found from this yeast: Homologous recombination – the prevention of damage to and the repair of DNA – both actions are considered a potential anti-cancer therapy. Now the race is on to take Brewer’s yeast and make it a patented medication…
Discovering the Secrets of Tumor Growth
Jan. 24, 2013 ”” Scientists at the University of Copenhagen’s Center for Healthy Ageing have identified a compound that blocks the expression of a protein without which certain tumours cannot grow. This compound has the potential as an anticancer agent according to the research published in the journal CHBIOL: Chemistry and Biology this week.
Now for the first time scientists have been able to turn off the BLM function in cells using an inhibitor called ML216, which stops cells that express BLM from multiplying, leaving cells without BLM alone.
Tumour treatment one step closer
Professor Ian D. Hickson, who led the research says: “Sarcomas and especially osteosarcomas are notoriously difficult to treat. This compound has the potential to lead to a treatment that could stop such tumours growing.”
Professor Hickson’s team is now working on finding derivatives of the compound that will be more potent and suitable to use as a basis for a drug.
“Once we have the compound in the right form, the next step is to test it using mice as a model and then, all being well, to move on to a clinical trial. However, we are several years off having an actual treatment.” He says.
- Giang Huong Nguyen, Thomas S. Dexheimer, Andrew S. Rosenthal, Wai Kit Chu, Dharmendra Kumar Singh, Georgina Mosedale, CsanÃ¡d Z. Bachrati, Lena Schultz, Masaaki Sakurai, Pavel Savitsky, Mika Abu, Peter J. McHugh, Vilhelm A. Bohr, Curtis C. Harris, Ajit Jadhav, Opher Gileadi, David J. Maloney, Anton Simeonov, Ian D. Hickson. A Small Molecule Inhibitor of the BLM Helicase Modulates Chromosome Stability in Human Cells. Chemistry & Biology, 2013; 20 (1): 55 DOI:10.1016/j.chembiol.2012.10.016
PLoS One. 2010; 5(11): e15380. Published online 2010 November 9. doi: 10.1371/journal.pone.0015380
The Roles of the Saccharomyces cerevisiae RecQ Helicase SGS1 in Meiotic Genome Surveillance
The Saccharomyces cerevisiae RecQ helicase Sgs1 is essential for mitotic and meiotic genome stability. The stage at which Sgs1 acts during meiosis is subject to debate. Cytological experiments showed that a deletion of SGS1 leads to an increase in synapsis initiation complexes and axial associations leading to the proposal that it has an early role in unwinding surplus strand invasion events. Physical studies of recombination intermediates implicate it in the dissolution of double Holliday junctions between sister chromatids.
In this work, we observed an increase in meiotic recombination between diverged sequences (homeologous recombination) and an increase in unequal sister chromatid events when SGS1 is deleted. The first of these observations is most consistent with an early role of Sgs1 in unwinding inappropriate strand invasion events while the second is consistent with unwinding or dissolution of recombination intermediates in an Mlh1- and Top3-dependent manner. We also provide data that suggest that Sgs1 is involved in the rejection of ”˜second strand capture’ when sequence divergence is present. Finally, we have identified a novel class of tetrads where non-sister spores (pairs of spores where each contains a centromere marker from a different parent) are inviable. We propose a model for this unusual pattern of viability based on the inability of sgs1 mutants to untangle intertwined chromosomes. Our data suggest that this role of Sgs1 is not dependent on its interaction with Top3. We propose that in the absence of SGS1 chromosomes may sometimes remain entangled at the end of pre-meiotic replication. This, combined with reciprocal crossing over, could lead to physical destruction of the recombined and entangled chromosomes. We hypothesise that Sgs1, acting in concert with the topoisomerase Top2, resolves these structures.
This work provides evidence that Sgs1 interacts with various partner proteins to maintain genome stability throughout meiosis.
AND READ ON…
Mech Ageing Dev. 2008 Jul-Aug;129(7-8):425-40. doi: 10.1016/j.mad.2008.03.003. Epub 2008 Mar 15.
Homologous recombination and maintenance of genome integrity: cancer and aging through the prism of human RecQ helicases.
Committee on Genetics, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA
Homologous recombination (HR) is a genetic mechanism in somatic cells that repairs DNA double-strand breaks and restores productive DNA synthesis following disruption of replication forks. Although HR is indispensable for maintaining genome integrity, it must be tightly regulated to avoid harmful outcomes. HR-associated genomic instabilities arise in three human genetic disorders, Bloom syndrome (BS), Werner syndrome (WS), and Rothmund-Thomson syndrome (RTS), which are caused by defects in three individual proteins of the RecQ family of helicases, BLM, WRN, and RECQL4, respectively. Cells derived from persons with these syndromes display varying types of genomic instability as evidenced by the presence of different kinds of chromosomal abnormalities and different sensitivities to DNA damaging agents. Persons with these syndromes exhibit a variety of developmental defects and are predisposed to a wide range of cancers. WS and RTS are further characterized by premature aging. Recent research has shown many connections between all three proteins and the regulation of excess HR. Here, we illustrate the elaborate networks of BLM, WRN, and RECQL4 in regulating HR, and the potential mechanistic linkages to cancer and aging.