We’re taking time to get to know the members of the GSA’s Early Career Scientist Committees. Join us to learn more about our early career scientist advocates.

Daniel J. Gironda

Policy and Advocacy Subcommittee

Wake Forest School of Medicine

Research Interest: Metastasis, the spread of cancer from a primary tumor to a secondary organ site, is the number one cause of death among cancer patients. How can we monitor this process and prevent it from happening in the first place? My current research aims to explore the genetic mechanisms and identify genetic vulnerabilities in patients with peritoneal surface malignancy (PSM). PSM is an aggressive type of metastatic spread that presents as multiple tumors growing on multiple sites throughout the abdominal cavity. Given that each individual patient, as well as each individual tumor, is genetically unique, we can aggregate and compare PSM tumors across pre-treated patients to identify common pathways of tumor growth and potentially targetable genes of interest. Moving forward, we hope to accumulate large sets of sequencing information on these tumors to which we can utilize the newfound vulnerabilities for therapeutic applications.

As a second-year doctoral student, I aspire to become an expert in genomic and transcriptomic analyses for elucidating the biological pathways of PSM. To do this, our lab collaborates with the Wake Forest Organoid Research Center (WFORCE) to create patient-derived tumor organoids (PTOs) for individual tumor modelling. Because the cells used to create the PTOs are isolated from each individual tumor from each patient, the PTO is one of the most physiologically relevant tumor models for precision medicine to date. With our PTO models, we will perform drug screening assays, followed by sequencing techniques, to determine the biological mechanisms that select for chemoresistance, metastasis, and recurrence. Through the isolation and sequencing of these PTOs after primary surgery, we hope to identify novel gene clusters that can tailor treatment at the individual patient level.

As a PhD-trained scientist, you have many career options. What interests you the most?

Multiple areas interest me. However, given the instability of funding in academia, pursuing a career in science policy is of high interest. Despite improvements in the availability of resources for young scientists, the funding infrastructure is not well equipped to continuously promote innovation. With the current R01 (the primary and oldest grant offered by the NIH) acceptance rate of ~8%, we are narrowing the playing field for potentially transformative biomedical research due to the restrained budget. However, what if we were to reallocate resources from state or federal institutions with significant financial surpluses to create a better funded environment for prospective research? Instead of allowing the average taxpayer’s dollars to die with these surpluses, we could optimize the distribution of funds to support humanity-promoting research and education. As a playmaker in the fund allocation decision process, I hope to open a fountain of resources for up-and-coming scientists. By highlighting the importance of new research, as well as transparently showing how the funds will be distributed, more interest in the realm of research will be generated and will promote the relevance of game-changing projects.

If a position in science policy is not in my cards, pursuing a director role for clinical research and development (R&D) at a startup biotech company would be of high interest as well. Similar to academic faculty members, clinical R&D directors have a fair amount of freedom to direct their own research. Because this position is in private industry, there is much more flexibility for funding one’s research while still being free to collaborate with academic institutions. Of course, like any position, it is highly competitive, and one has to stay prolific in terms of patents, grants, and scientific publications. Yet, with the freedom to perform independent research with more access to resources, working in industry seems to be a great option for up-and-coming scientists. But hey, I am still early on in the process—you can never predict where you will end up next, you know?  

In addition to your research, how do you want to advance the scientific enterprise?

Actively communicating and exchanging with the general public is the most proactive way to advance the scientific enterprise. Generating interest, or sharing foundational knowledge as to why one should be interested, is the most important factor for selling an idea or product. Educating individuals who are opposed to new scientific endeavors is the best way to create confidence and trust around the field, as well as to better demonstrate the significance of new research. As an educator across multiple disciplines throughout my undergraduate career, I see no better way to give back to the general population as an academic than by educating through open dialogue. Science is only as powerful as the audience it reaches. Integrating non-scientists into the scientific thought process—as well as having open discussions about past beneficial discoveries, our current state of scientific progress, and our future—can expand their way of viewing science as a whole. Similar to TEDx and other platforms for sharing thoughts and ideas, I would want to go to underserved communities and organize town halls to have these conversations. More often than not, the disconnect between scientists and the average person is due to their lack of candid conversations—there is not much overlap between our day-to-day lives. However, this lack of human connection hampers our ability to reach out to the general public. As humans, we need to find a general understanding amongst one another before any progress can be made. We cannot unify scientists and non-scientists until we open the door and speak candidly. We not only wish to educate but also hope to inspire the average individual and open their mind as to what heights mankind can reach. As Johann Wolfgang von Goethe wrote, “Knowing is not enough; we must apply. Willing is not enough; we must do.” Through open and honest dialogue with the general public, I hope to expand general interest in the scientific community and enroll others to contribute to the field.

As a leader within the Genetics Society of America, what do you hope to accomplish?

First and foremost, I want to leverage the GSA platform by promoting better STEM education at the elementary, middle, and high school levels in my local community, as well as the greater state and country. Due to the pandemic, many young students have been deprived of a traditional education—one in which they can directly interact and converse with their educators. Hands-on instruction is crucial to the learning process, and educators across all age groups recognize that online schooling is not enough to meet these needs. As a member of the policy and advocacy subcommittee, I hope to speak with local politicians on how to improve our school systems through a hands-on approach. Educational reconfiguration has to start with how we train our teachers. This training may be done through a thought-out, rigorous, and standardized curriculum across the board for each subject type, in addition to increasing the number of resources given to these educators and students to facilitate the revamping. Educating young scientists and future members of the work force follows a pyramid structure—one is only as knowledgeable as the base on which one’s knowledge is built. By promoting stronger analytical skills from a young age, we would provide our kids with a framework that will build a better tomorrow.

Second, I wish to collaborate with and expand the current research network I am involved in. Collaboration is the key to validating strong science and keeping the scientific community liable. It is fine to have strong science and prestige as an independent force, but what is its true value if others cannot replicate and validate the legitimacy of one’s findings? As a leader within the GSA, I aspire to be a strong proponent in increasing scientific stringency, rigor, and accountability across multiple research disciplines.

I am always up for talking about science, politics, or general life questions with awesome people. Reach out to me with the links below to connect!

Previous leadership experience

Presidential member of the Genetics Society of America (2022–Present)

Co-chair for the Skin, Wound Healing, and Inflammation Scientific session, Tissue Engineering and Regenerative Medicine International Society-Americas (TERMIS-AM) 2022 annual meeting

Recipient of the Outstanding New Member award, Rutgers University, New Brunswick: Office of Fraternity and Sorority Affairs (2018)

Lead tutor at the Livingston Writing Center of Rutgers University, New Brunswick (2016–2018)

Graduate of the Torch Academy, a goal-setting and leadership training program (2012)

You can contact Daniel J. Gironda on Twitter @DanielJGironda, or on LinkedIn @DanielJGironda, and read their publications here.

New evidence for genome instability in fly tumors suggests key similarities—and differences—from human disease processes.

Human cancers display a variety of abnormal genomic features, including increased numbers of single nucleotide variants (SNVs) and copy number variants (CNVs). However, a 2014 study on a fruit fly tumor detected no elevation of SNVs or CNVs compared to non-tumor tissues, raising questions about how well the fly tumors, which are sometimes used in cancer research, represent cancer in humans. Rossi et al. investigated whether this was generally the case in malignant neoplasms in flies by sequencing the genomes of 17 such tumors caused by mutations in four different genes.

To address this question, the researchers used a process called allografting: they dissected tumors from fly larvae, then implanted them into the abdomens of adult flies. Each time the tumors filled up the abdomens of their hosts, the tumors were removed, and some of the tumor cells were allografted again into new fly hosts. This approach allowed them to monitor which types of mutations accumulate over many rounds of cell division. Without these successive iterations of allografting, they would have been limited to studying mutations that occur over the comparatively short lifespan of the hosts.

In all of the allografted tumors, the researchers found increases in SNVs and CNVs similar in number to those seen in human cancers, and in the case of CNVs, with a similar size distribution. Also as in humans, the increases in the number of mutations varied from one tumor type to the next. However, they also found that the CNVs weren’t distributed in any discernable pattern, no two allografts had SNVs affecting the same genes, and the CNVs and SNVs often weren’t retained from one allograft to later allografts. This implies that these mutations may merely be byproducts of genome instability in the tumors and thus don’t contribute to malignancy, whereas in humans, it’s thought that the accumulation of such mutations as tumors age is a driver of malignancy.

One important consideration, though, is that studies looking for genetic variants correlated with cancer in humans often have much larger sample sizes, which might reveal associations this fly study could not identify. Still, because flies are important model organisms for cancer research, furthering our understanding of the similarities and differences between human and fly tumors, as Rossi et al. have done, is essential.

CITATION:

Drosophila Larval Brain Neoplasms Present Tumour-Type Dependent Genome Instability
Fabrizio Rossi, Camille Stephan-Otto Attolini, Jose Luis Mosquera, Cayetano Gonzalez
G3: Genes|Genomes|Genetics 2018 8: 1205-1214; https://doi.org/10.1534/g3.117.300489
http://www.g3journal.org/content/8/4/1205

Yeast study suggests faulty proofreading is not to blame for link between cancer and DNA polymerase ε variants.

Accurate DNA replication is a matter of life and death. The polymerases responsible for replicating DNA have built-in safeguards to defend genome integrity, including proofreading activities to correct their own errors. Abnormally error-prone variants of DNA polymerase ε are linked to several types of cancer, and a popular hypothesis is that this is due to diminished proofreading ability. But new evidence published in G3 suggests otherwise.

In a yeast study of several mutant forms of DNA polymerase ε (Polε) associated with cancers, Barbari et al. show that the increased mutation rates of these wayward polymerases may not result from weakened proofreading alone. In fact, the vast majority of Polε exonuclease domain variants the group studied increased the yeast’s mutation rate more than a Polε variant that completely lacked proofreading ability did. Previous in vitro studies also showed that although the exonuclease activity Polε uses to excise mistakes is reduced in most of these variants, it is not eliminated. This means there must be other problems with these cancer-linked variants, the nature of which remain a mystery for now—though one clue is that they have amino acid substitutions in the DNA-binding cleft of Polε’s exonuclease domain.

The researchers also observed a correlation between the amount a Polε variant increased the yeast mutation rate and how common the variant was in tumors from a set of studies involving over 13,000 cases. In contrast, previous research found vastly different incidences in tumors among variants with similar impacts on exonuclease activity, providing further evidence that proofreading defects aren’t behind all cancers linked to faulty Polε. Barbari et al. don’t make any bold claims about what does cause these cancers, but given that 6% of colorectal tumors and 7% of endometrial tumors have Polε mutations, it’s clear further efforts must be dedicated to finding out.

CITATION:

Functional Analysis of Cancer-Associated DNA Polymerase ε Variants in Saccharomyces cerevisiae
Stephanie R. Barbari, Daniel P. Kane, Elizabeth A. Moore, Polina V. Shcherbakova
G3: Genes|Genomes|Genetics 2018 8: 1019-1029; https://doi.org/10.1534/g3.118.200042
http://www.g3journal.org/content/8/3/1019

When a mutation arises in an egg or sperm cell, it could be evolutionarily important. But if a mutation occurs in somatic tissue instead, the result could be cancer. Mutations in the germline and soma not only have contrasting consequences, they also arise at different rates that may reflect the balance of DNA damage and repair pathways in different tissue types. In the September issue of GENETICS, Chen et al. predict gene mutation rates in different tissues and find that high expression increases mutation rates in the germline, but not in somatic tissue.  

The first step was to obtain a reliable estimate of the mutation rate in both germ cells and somatic tissues. The researchers relied on a set of germline mutations, previously identified using exome data from thousands of sets of parents and children. Any variation that was unique to the children must be caused by germline mutation in either the father or mother. To identify somatic mutations, the researchers analyzed three different cancer samples that included whole exome sequence of both normal and malignant cells. Variation unique to either tissue type predates the tumor and should be due to somatic mutations.

A statistical model that evaluated how well various factors predict the mutation rate revealed a key difference. In germ cells, a high gene expression level was linked to a higher mutation rate, but the opposite was observed in somatic tissues. Though the magnitude of the effect varied in the three different cancer types, there was always a negative correlation with expression. Other factors also contributed differently to mutation in the germline and somatic tissues, including GC content for the germline and replication timing in the soma.

Gene expression level probably affects mutation rate because the DNA double helix unzips to accommodate transcription machinery, making the individual strands more vulnerable to mutagens, and because there is a dedicated repair mechanism to fix DNA damage that occurs in transcribed regions. The opposite effects of expression level on mutation rates suggests germline and somatic tissues have marked differences in the balance between damage and repair. For example, expression may be more mutagenic in the germline, or repair mechanisms may be more efficient in the soma. There could even be unidentified DNA damage repair processes that are unique to certain tissues. Though somatic mutations can’t be passed down to the next generation like germline mutations, they are the root cause of most cancers. Quickly and correctly repairing this DNA damage is vital for an organism’s survival.

CITATION:

Contrasting Determinants of Mutation Rates in Germline and Soma

Chen Chen, Hongjian Qi, Yufeng Shen, Joseph Pickrell, and Molly Przeworski

GENETICS September 1, 2017. 207 (1): 255-267

https://doi.org/10.1534/genetics.117.1114

http://www.genetics.org/content/207/1/255

Cancer profoundly scars the genome of an affected cell. Amplification and overexpression of chunks of DNA sequence are common—but it’s not always clear whether these changes are directly involved in the disease or byproducts of some other malfunction. Further complicating the search for treatments, many genes that are altered in cancer cells are involved in multiple biochemical pathways, making it difficult to know which to target with drugs. To shed light on one such pathway, researchers whose work is featured in the October issue of GENETICS used a clever assay in budding yeast.

The researchers focused on CKS1B, a cell cycle gene that is often found in many copies in cancer cells. Cell cycle dysregulation is common in cancers, so amplification of CKS1B may contribute to pathogenesis. To identify pathways that are important when CKS1B is amplified, the researchers overexpressed the yeast homolog, CKS1, in yeast strains from a knockout collection (in which a different gene is mutated in each strain) and looked for strains that failed to grow. These strains struggle to function when CKS1 levels are boosted, indicating that there is a genetic interaction between CKS1 and each strain’s mutated gene (technically called synthetic dosage lethality). This search revealed interactions with pathways that affect cell viability or growth, both crucial to rapidly-dividing cancer cells.

By targeting genes that cause lethality when disrupted in cells overexpressing CKS1B, it might be possible to selectively wound cancer cells that have amplified CKS1B. Many of the interacting genes found in the screen are conserved from yeast to humans. One of the genes identified is cdc5, an ortholog of mammalian PLK1, and they discovered that overexpression of CKS1B increased the sensitivity of cancer cells to Plk1 inhibition. Thus, the authors suggest that CKS1B amplification has the potential to be used as a biomarker of cancer susceptibility to Plk1 inhibitors, a class of cancer drugs that is currently under development. Perhaps one day, the genetic links identified in yeast might help clinicians personalize cancer treatment in people.

CITATION:

Reid, R.; Du, X.; Sunjevaric, I.; Rayannavar, V.; Dittmar, J.; Bryant, E.; Maurer, M.; Rothstein, R. A Synthetic Dosage Lethal Genetic Interaction Between CKS1B and PLK1 Is Conserved in Yeast and Human Cancer Cells.
GENETICS, 204(2), 807-819.
DOI:10.1534/genetics.116.190231
http://www.genetics.org/content/204/2/807

The detonation of atomic bombs over the Japanese cities of Hiroshima and Nagasaki in August 1945 resulted in horrific casualties and devastation. The long-term effects of radiation exposure also increased cancer rates in the survivors. But public perception of the rates of cancer and birth defects among survivors and their children is in fact greatly exaggerated when compared to the reality revealed by comprehensive follow-up studies. The reasons for this mismatch and its implications are discussed in a Perspectives article on the Hiroshima/Nagasaki survivor studies published in the August issue of GENETICS.

“Most people, including many scientists, are under the impression that the survivors faced debilitating health effects and very high rates of cancer, and that their children had high rates of genetic disease,” says Bertrand Jordan, an author and a molecular biologist at UMR 7268 ADÉS, Aix-Marseille Université/EFS/CNRS, in France. “There’s an enormous gap between that belief and what has actually been found by researchers.”

Dr. Jordan’s article contains no new data, but summarizes over 60 years of medical research on the Hiroshima/Nagasaki survivors and their children and discusses reasons for the persistent misconceptions. The studies have clearly demonstrated that radiation exposure increases cancer risk, but also show that the average lifespan of survivors was reduced by only a few months compared to those not exposed to radiation. No health effects of any sort have so far been detected in children of the survivors.

Approximately 200,000 people died in the bombings and their immediate aftermath, mainly from the explosive blast, the firestorm it sparked, and from acute radiation poisoning. Around half of the those who survived subsequently took part in studies tracking their health over their entire lifespan. These studies began in 1947 and are now conducted by a dedicated agency, the Radiation Effects Research Foundation (RERF), with funding from the Japanese and U.S. governments. The project has followed approximately 100,000 survivors, 77,000 of their children, plus 20,000 people who were not exposed to radiation.

This massive data set has been uniquely useful for quantifying the risks of radiation because the bombs served as a single, well-defined exposure source, and because the relative exposure of each individual can be reliably estimated using the person’s distance from the detonation site. The data has been particularly invaluable in setting acceptable radiation exposure limits for nuclear industry workers and the general public.

Cancer rates among survivors was higher compared to rates in those who had been out of town at the time. The relative risk increased according to how close the person was to the detonation site, their age (younger people faced a greater lifetime risk), and their sex (greater risk for women than men). However, most survivors did not develop cancer. Incidence of solid cancers between 1958 and 1998 among the survivors were 10% higher, which corresponds to approximately 848 additional cases among 44,635 survivors in this part of the study. However, most of the survivors received a relatively modest dose of radiation. In contrast, those exposed to a higher radiation dose of 1 Gray (approximately 1000 times higher than current safety limits for the general public) bore a 44% greater risk of cancer over the same time span (1958-1998). Taking into consideration all causes of death, this relatively high dose reduced average lifespan by approximately 1.3 years.

Although no differences in health or mutations rates have yet been detected among children of survivors, Jordan suggests that subtle effects might one day become evident, perhaps through more detailed sequencing analysis of their genomes. But it is now clear that even if the children of survivors do in fact face additional health risks, those risks must be very small.

Jordan attributes the difference between the results of these studies and public perception of the long-term effects of the bombs to a variety of possible factors, including historical context.

“People are always more afraid of new dangers than familiar ones,” says Jordan. “For example, people tend to disregard the dangers of coal, both to people who mine it, and to the public exposed to atmospheric pollution. Radiation is also much easier to detect than many chemical hazards. With a hand-held geiger counter, you can sensitively detect tiny amounts of radiation that pose no health risk at all.”

Jordan cautions that the results should not be used to foster complacency about the effects of nuclear accidents or the threat of nuclear war. “I used to support nuclear power until Fukushima happened,” he says. “Fukushima showed disasters can occur even in a country like Japan that has strict regulations. However, I think it’s important that the debate be rational, and I would prefer that people look at the scientific data, rather than gross exaggerations of the danger.”

CITATION

The Hiroshima/Nagasaki survivor studies: discrepancies between results and general perception

Bertrand R. Jordan

GENETICS, August 2016, Vol. 203, 1505-1512; doi: 10.1534/genetics.116.191759

http://www.genetics.org/content/203/4/1505

With about 1 in 8 women in the United States expected to develop breast cancer in their lifetime, breast cancer remains the most common malignancy in women. Though heavily studied, its complexity creates significant challenges to diagnosis, prognosis, and treatment. One of the major problems is that causal DNA mutations of the disease vary from case to case. Human breast cancer falls into four major molecular subtypes (luminal A and B, HEWithR2-enriched, and basal-like), and these subtypes are associated with significant differences in prognosis and survival.

In the December issue of GENETICS, Li et al. explored the possibility that overarching gene regulatory mechanisms modulate the varying pathways of the four major breast cancer subtypes.

The researchers used publicly available sequencing, gene expression, and clinical data collected from over 3,000 human breast cancer cases across three cohorts.  To this data, they applied the methods of machine learning, a powerful tool for selecting a small number of genes that can discriminate tumor samples into the four subtypes, and mutual information modeling, a method to accurately capture nonlinear interactions between regulators and their regulons .

They identified 16 master regulator genes (MR16) that shape different tumor subtypes. The master regulators are transcription factor genes that play a pivotal role in modulating downstream pathways or gene networks. Gene expression patterns from all three cohorts indicated that the MR16 can be divided into two groups that regulate cancer-related genes in opposite directions. For example, one group up-regulates cell cycle gene expression in only the HER2-enriched and the basal-like subtypes. Conversely, another group of the MR16 down-regulates cell cycle gene expression in those same subtypes. These results reveal a gene regulatory program that affects tumor progression in breast cancer.

Li et al. also sought to associate DNA mutations with gene regulatory pathway changes in tumor subtypes. They found an association of mutations of the gene TP53 with the previously described upregulation of cell cycle pathways in HER2-enriched and basal-like subtypes. This suggests that cell cycle pathway changes may be the characteristic genomic changes in the two subtypes, which opens a potential avenue to design new therapies.

Taken together, these findings help clarify gene regulatory programs in breast cancer, bringing us closer to using precision medicine to treat this complex disease.

CITATION

Li, R., Campos, J. & Iida, J. (2015) A Gene Regulatory program in Human Breast Cancer. Genetics, 201(4), 1341-1348. doi:10.1534/genetics.115.180125

http://www.genetics.org/content/201/4/1341

The mutations that drive cancer formation are often found in “hub” genes that regulate many aspects of cell growth and survival. But these key genes are not always good therapeutic targets — some are even considered “undruggable.” In the latest issue of GENETICS, Bailey et al. identify a strategy for fighting cancer cells that carry a mutation in one such difficult-to-target hub gene, FBW7. This tumor suppressor is mutated in approximately 6% of all cancer cases, including around a third of cases of T-cell acute lymphocytic leukemia and cholangiocarcinoma.

The FBW7 protein is part of the SCF ubiquitin ligase complex that marks other proteins for selective degradation. Many of these substrates are involved in oncogenesis (cancer formation), including the cell cycle regulator cyclin-E and the cell death inhibitor MCL1. Without FBW7 keeping them in check, these cancer-promoting proteins accumulate in the cell and can trigger uncontrolled division.

Even though FBW7’s tumor suppressor function is well understood, little is known about how the mutant cells might be targeted for treatment. That’s because inactivating the function of a tumor suppressor gene (e.g. with a drug) would encourage, not inhibit cancer, while many of FBW7’s oncogenic substrates are themselves difficult to manipulate with pharmaceuticals.

The authors approached this problem by screening for “synthetic lethal” partners of FBW7, which are proteins needed for cell survival when FBW7 is non-functional. They screened approximately 16,000 human genes by knocking down their expression in fbw7 mutant colorectal cancer cells and FBW7 wild-type cells, looking for proliferation effects that were specific to the mutants.

One of the candidates identified in the screen was BUBR1, which encodes a component of the mitotic spindle assembly checkpoint (SAC). This checkpoint prevents cell division from proceeding until all chromosomes are correctly attached to the spindle apparatus. When BUBR1 expression is knocked down in fbw7 mutant cells, the cells proliferate slower than wild-type and become more prone to losing and gaining chromosomes through cell division errors. This vulnerability of fbw7 cells was confirmed by tests with other SAC components.

Why do fbw7 cells have such a critical need for spindle assembly surveillance? One part of the answer is that the cells have dysregulated cyclin E. This is suggested by the fact that dampening expression of cyclin E rescues fbw7 mutant cells from their dependence on BUBR1. Cyclin E is not the whole story, however, because boosting levels of this protein alone was not enough to make FBW7 wild-type cells sensitive to SAC loss; this was only achieved by overexpressing another FBW7 substrate, MCL1, along with a form of cyclin E sometimes seen in cancer cells.

The results show that in this cell culture model, fbw7 mutant cells depend on the SAC for their cancerous potential, likely because they have cell cycle defects that necessitate extra time for spindle assembly. Without this breathing room, the dividing cells may be more prone to lethal chromosome segregation mistakes.
The authors suggest that other cancer cell types — many of which experience chronic chromosome instability — might also depend on the SAC. They suggest that exploiting this weak spot could be a promising strategy for developing anticancer drugs, especially since blocking SAC function could have fewer side-effects than existing anti-mitotic drugs. Though there is a long way to go before this idea could be applied in the clinic, the “undruggable” target FBW7 may have pointed the way to a more accessible chink in cancer’s armor.

A model for SAC dependence in cells lacking FBW7. From Baikey et al. (A) FBW7 +/+ cells in prometaphase efficiently align their chromosomes and correctly segregate properly in anaphase with less reliance on the SAC. FBW7 −/− cells have an increase in cyclin E, which causes problems in mitosis and may lead to SAC activation. FBW7 −/− cells can survive prolonged SAC activation in part because of stabilization of MCL1 allowing more time for chromosome alignment. (B) A decrease in SAC activation by knockdown of BUBR1 may significantly shorten the time available for chromosome alignment in FBW7 −/− cells, resulting in improper chromosome segregation and intolerable levels of chromosome instability.

Citation:

Bailey, M. L., Singh, T., Mero, P., Moffat, J., & Hieter, P. (2015). Dependence of Human Colorectal Cells Lacking the FBW7 Tumor Suppressor on the Spindle Assembly Checkpoint. Genetics, 201(3), 885-895. Doi: 10.1534/genetics.115.180653

http://www.genetics.org/content/201/3/885.full