Tug of war between Parkinson’s protein and growth factors

A “tug of war” situation exists between Parkinson's provocateur protein alpha-synuclein and the growth factor Read more

From stinging to soothing: fire ant venom may lead to skin treatments

Compounds derived from fire ant venom can reduce skin thickening and inflammation in a mouse model of psoriasis, Emory and Case Western scientists have Read more

Troublemaker cells predict immune rejection after kidney transplant

Evidence is accumulating that the presence of certain "troublemaker" memory T cells can predict the likelihood of belatacept-resistant immune Read more

DNA repair

Cancer drug discovery: targeting DNA repair

Standard anticancer treatments, such as chemotherapy, target rapidly dividing cells by damaging their DNA. A newer strategy is to undercut cancer cells’ ability to repair DNA damage.

Radiation oncologist David Yu, MD, PhD

Winship Cancer Institute investigators led by David Yu, MD, PhD have identified a distinct function in DNA double strand break repair for an enzyme called SAMHD1. Depleting or inhibiting SAMHD1 could augment anticancer treatments that induce DNA double-strand breaks, such as ionizing radiation or PARP inhibitor drugs, they suggest. Ionizing radiation is a mainstay of cancer treatment and PARP inhibitors are being developed for several cancer types.

The findings were published this week in Cell Reports (open access).

SAMHD1 was known for its ability to chop up the building blocks of DNA, and had come to the attention of virologists because it limits the ability of retroviruses such as HIV to infect some cell types. The first author of the paper, postdoc Waaqo Daddacha, PhD, previously studied SAMHD1 with virologist Baek Kim, PhD, professor of pediatrics.

Cancer researchers had already sought to harness a retroviral protein called Vpx, which viruses evolved to disable SAMHD1. Acute myeloid leukemia cells use SAMHD1 to get rid of the drug cytarabine, so Vpx can sensitize AML to that drug. The Cell Reports paper shows that virus-like particles carrying Vpx could be deployed against other types of cancer, in combination with agents that induce DNA double-strand breaks. Read more

Posted on by Quinn Eastman in Cancer Leave a comment

SUMO wrestling enzyme important in DNA repair

The DNA in our cells is constantly being damaged by heat, radiation and other environmental stresses, and the enzyme systems that repair DNA are critical for life. A particularly toxic form of damage is the covalent attachment of a protein to DNA, which can be triggered by radiation or by anticancer drugs.

Keith Wilkinson, PhD

Emory biochemist Keith Wilkinson and colleagues have a paper this week in the journal eLife probing how a yeast protein called Wss1 is involved in repairing DNA-protein crosslinks. The researchers show how Wss1 wrestles with a protein tag called SUMO on the site of the DNA damage, and how Wss1 and SUMO are involved in the cleanup process.

Three interesting things about this paper:

*The paper grew out of first author Maxim Balakirev’s sabbatical with Wilkinson at Emory. Balakirev’s home base is at the CEA (Alternative Energy and Atomic Energy Commission) in Grenoble, France.

* Since many cancer chemotherapy drugs induce protein-DNA cross links, an inhibitor of cross link repair could enhance those drugs’ effectiveness. On the other side of the coin, mutations in a human gene called Spartan, whose sequence looks similar to Wss1’s, cause premature aging and susceptibility to liver cancer. Whether the Spartan-encoded protein has the same biochemical activity as Wss1 is not yet clear.

*SUMO stands for “small ubiquitin-like modifier”. The eLife digest has an elegant explanation of what’s happening: Read more

Posted on by Quinn Eastman in Cancer Leave a comment

When cells fix DNA the wrong way

Cells sometimes “fix” DNA the wrong way, creating an extra mutation, Emory scientists have revealed.

Biologist Gray Crouse, PhD, and radiation oncologist Yoke Wah Kow, PhD, recently published a paper in Proceedings of the National Academy of Sciences that shows how mismatch repair can introduce mutations in nondividing cells. Their paper was recognized by the National Institute of Environmental Health Sciences as an extramural paper of the month. The first author is lead research specialist Gina Rodriguez.

In DNA, a mismatch is when the bases on the two DNA strands do not conform to Watson-Crick rules, such as G with T or A with C. Mismatches can be introduced into DNA through copying errors as well as some kinds of DNA damage.

If the cell “fixes” the wrong side, that will introduce a mutation (see diagram). So how does the cell know which side of the mismatch needs to be repaired? Usually mismatch repair is tied to DNA replication. Replication enzymes appear to somehow mark the recently copied strand as being the one to replace — exactly how cells accomplish this is an active area of research.

In some situations, mismatch repair could introduce mutations into DNA.

Overall, mismatch repair is a good thing, from the point of view of preventing cancer. Inherited deficiencies in mismatch repair enzymes lead to an accumulation of mutations and an increased risk of colon cancer and other types of cancer.

But many of the cells in our bodies, such as muscle cells and neurons, have stopped dividing more or less permanently (in contrast with the colon). That means they no longer need to replicate their DNA. Other cells, such as resting white blood cells, have stopped dividing temporarily. Mutations in nondividing cells may have implications for aging and cancer formation in some tissues.

Through clever experimental design, Crouse’s team was able to isolate examples of when mismatch repair occurred in the absence of DNA replication.

As the NIEHS Newsletter notes:

“The researchers introduced specific mispairs into the DNA of yeast cells in a way that let them observe the very rare event of non-strand dependent DNA repair. They found that mispairs, not repaired during replication, sometimes underwent mismatch repair later when the cells were no longer dividing. This repair was not strand dependent and sometimes introduced mutations into the DNA sequence that allowed cells to resume growth. In one case, they observed such mutations arising in cells that had been in a non-dividing state for several days.”

Although the Emory team’s research was performed on yeast, the mechanisms of mismatch repair are highly conserved in mammalian cells. Their results could also shed light on a process that takes place in the immune system called somatic hypermutation, in which mutations fine-tune antibody genes to make the most potent antibodies.

Posted on by Quinn Eastman in Cancer 2 Comments

The challenges of graduate school

Biochemist Paul Doetsch’s recent appearance in a Science magazine feature on laboratory leadership led to a conversation with him about the challenges of graduate school.

He emphasized that scientific research is a team sport, and brilliance on the part of the lab head may not yield fruit without a productive relationship with the people in the lab. Doetsch suggested talking with Lydia Morris, a graduate student in the Genetics and Molecular Biology graduate program. Morris has been working in Doetsch’s lab for several years and is about to complete her degree. She has been examining the in vivo distribution of DNA repair proteins.

In this video, Morris and Doetsch talk about the differences between turn-the-crank and blue-sky projects, and the importance of backup projects, communications, high expectations and perseverance.

Posted on by Quinn Eastman in Cancer Leave a comment

Lab management: leading by example

Paul Doetsch, PhD

Cancer researcher Paul Doetsch is a prominent voice in a recent feature in Science magazine’s Careers section. The article gives scientists who are setting up their laboratories advice on how to manage their laboratories and lead by example.

Doetsch holds a distinguished chair of cancer research and is associate director for basic research at Winship Cancer Institute. His research on how cells handle DNA damage has provided insights into mechanisms of tumor formation and antibiotic resistance. His lab includes five graduate students, two senior postdocs and one technical specialist.

From the article:

Doetsch says that he tries to maintain a lab culture that provides technicians, students, postdocs, and research faculty a sense of “ownership” of their projects and to give the message everyone is making a significant contribution to the research enterprise, regardless of their specific title or role.
“I make it a point to walk around my lab several times a day to chat with my group and hold individual weekly research meetings with each member to get an update of their progress and provide them with direct, constructive feedback on their activities,” he says. “I always strongly encourage everyone to discuss their results and other issues affecting their project with their lab colleagues and to not hesitate to disagree with me when necessary.”

Author Emma Hitt was herself a graduate student at Emory.

Posted on by Quinn Eastman in Uncategorized Leave a comment

DNA copying problems explain muscular dystrophy mutations

Geneticist Madhuri Hegde and her colleagues have a paper in the journal Genome Researchthat addresses the question: where do copy number variations come from?

Madhuri Hegde, PhD

Copy number variations (CNVs), which are deletions or duplications of small parts of the genome, have been the subject of genetic research for a long time. But only in the last few years has it become clear that copy number variations are where the action is for complex diseases such as autism and schizophrenia. Geneticists studying these diseases are shifting their focus from short, common mutations (often, single nucleotide polymorphisms or SNPs) to looking at rarer variants such as CNVs. A 2009 discussion of this trend with Steve Warren and Brad Pearce can be found here.

Hegde is the Scientific Director of the Department of Human Genetics’ clinical laboratory. Postdoctoral fellow Arun Ankala is the first author. In the new paper, Ankala and Hegde examine rearrangements in patients’ genomes that arose in 62 clinical cases of Duchenne’s muscular dystrophy and several other diseases. Mutations in the DMD gene are responsible for Duchenne’s muscular dystrophy.

The pattern of the rearrangement hints what events took place in the cell beforehand, and hint that a problem took place during replication of the DNA. The signature is a tandem duplication of a short segment next to a large deletion, indicating how the DNA was repaired.

The authors note that the DMD locus is especially prone to these types of problems because it is much larger than other gene loci. The gene is actually the longest human gene known on the DNA level, covering 2.4 megabases (0.08 percent of the genome.)

Replication origins are where the DNA copying machinery in the cell starts unwinding and copying the DNA. Bacterial circular chromosomes have just one replication origin. In contrast, humans have thousands of replication origins spread across our chromosomes. In the discussion, the authors suggest that DNA copying problems may also explain duplications and historically embedded rearrangements of the genome.

Posted on by Quinn Eastman in Neuro Leave a comment