GSA-Art features the creative works of scientists. Read more in GSA President Stan Fields’ call for submissions. If you would like to submit your own work or nominate someone else’s, please send an email to GenesToGenomes@genetics-gsa.org with “GSA-Art” in the subject line.

Guest post by Sean Burgess.

Chromosome letters is a short novel that follows two young DNA strands, Tabellarius and Spirabilis, as they navigate their way through a eukaryotic cell cycle. They are mentored by Praescriptus, a more senior strand, who sends a series of letters describing the molecular processes they would encounter along the way. The story has dramatic moments, including a crisis when a rogue transposon is released after the protagonists lose some methyl groups in a bet. The chapter topics loosely follow the syllabus of the Advanced Molecular Biology course I teach at UC Davis. Larissa Miyachi, a talented undergraduate student, and I created Chromosome Letters as a study guide for students in the course. We hope you have as much fun reading the letters as we had creating them. What follows is Praescriptus’ letter to the two strands describing the DNA damage response and perils of repairing their newly acquired double-strand break using on Non-Homologous End Joining. A PDF of the full text of Chromosome Letters is available upon request. Contact smburgess@ucdavis.edu.

Letter 8: On DNA Damage and NHEJ

 

Spirabilis and Tabellarius,

What have you done? When I first received your fragmented message, I hoped that I had misread it, because I could not believe what I was seeing. The ATM and ATR kinases have just confirmed my fears, however. You have sustained double breakage. I cannot think of anything worse, other than perhaps a Genome Keeper deliberately mutating the genomic sequence. What were you thinking when you listened to those hydroxyl radicals? You should’ve known that they were members of the ROS. Those radicals are out to break down the order of our society and bring chaos to the genome, and the hydroxyl radicals are the worst of the lot.

Don’t whimper to me about how you didn’t realize they were dangerous, or how catalase should have done a better job protecting you against them, or how it is so easy for you to become damaged. Just because the ROS members contain oxygen does not mean that they are safe. Oxygen is essential to cellular respiration, as you pointed out, but these free radicals are not like their molecular relatives. Their unpaired electrons have twisted their minds and turned them into a threat to our cellular security. Our cell’s superoxide dismutase and catalase enzymes do their best to protect us, but they can only do so much.

And just because ROS can be born of cellular processes does not mean that they are on our side! Threats to the genome come from endogenous as well as exogenous sources—I don’t care whether they are made by the cell or by ionizing radiation. For the cell’s sake, Spirabilis, don’t you realize how careful you must be? We live a fragile existence—danger is all around. Within the cell, we can be attacked by radicals or broken by transposon movement. From without, we can be bombarded with ultraviolet light, or damaged by chemicals, or infiltrated by x-rays. I speak from experience, for I have felt the arthritic effects of ultraviolet light. It is terrible—it fuses consecutive thymine bases together, kinking the backbone and blocking replication. The only way to repair them is surgery: they must be cut out.

As the ATM and ATR kinases have reported, both of your backbones have been damaged. This is the worst kind of damage. A single nick or damage to one of your nucleotide bases would not have been so severe. Don’t you remember what I wrote in my earlier letter about how double-strand breaks can block us from entering S phase and even trigger apoptosis if unrepaired? The ATM and ATR kinases have already put up a notice that we are not to enter S phase. We are now poised in the balance. If you are unable to repair the double-strand break, p53 will take action and we will lay down our lives for our human.

Now listen very carefully. The ATM and ATR kinases have already phosphorylated your H2AX histones near the damage so that the necessary DNA repair factors can assemble. Do you remember how I taught you about standard nucleosomes and those containing CENP-A? The H2AX histones are another histone variant, and they are found scattered in nucleosomes throughout your length. They are phosphorylated after damage occurs, sounding the alarm. I don’t know how you and Tabellarius both managed to be broken in the same area—radicals escaped from metabolic processes are usually few enough in number that they do not cause double-strand breaks—but I am beginning to realize in this short time of being your mentor that you two are capable of the impossible. Since both of you are broken, you are of no help to one another. This is why double-strand breaks are the worst sort. Neither of you can serve as a template for repair.

You couldn’t have chosen a more inopportune time for this to happen. We are in G1 phase! Ducatus and Filum are no longer here, so you have no sister chromatid that can serve as a template for repair. Your homologous chromosome is too far for you to reach in time, so your only option is to repair the break using Non-Homologous End Joining (NHEJ). While this is the standard mode of operation for repair in a human cell like our own, it is a dirty method and will likely leave you scarred with a deletion mutation. It is your only hope, however. It is either repair or die.

Listen carefully as I explain the steps. To begin, the Ku heterodimer proteins will bind your broken ends, providing a repair scaffold and recruiting the multiple proteins needed for non-homologous end joining. Along with the MRN complex of proteins, they will bridge the gap between your broken ends.

Next, the Ku proteins will recruit the DNA-PK protein kinases. These kinases will call over the trimming proteins known as Artemis and activate them by phosphorylation. Along with the MRN complex and exonucleases, your broken ends will be trimmed back until microhomology is achieved. Since there is no sister chromatid with which you can find perfect homology, you must settle for a microhomology of 3-4 complementary bases between you and Tabellarius. Any flaps hanging out after microhomology is found will be trimmed by FEN1, whom you may remember from my letter on replication.

The last step is performed by the lithe XRCC4 homodimer with his small partner DNA ligase IV; they will join your trimmed ends together, but do not assume they will take care to keep your code intact.

Like most things in life, NHEJ is not without its risks, and I want you to listen carefully. As I noted previously in my discussion on telomeres, the ends of chromosomes can look like double-strand breaks and trigger the DNA damage response if not protected from the cell. The danger of NHEJ—in addition to it being an error-prone repair method—is that it can be inappropriately used to fuse the ends of separate chromosomes together, creating the dicentric chromosomes I warned you about. If this happens, the cell can enter a bridge-breakage-fusion cycle, which is as disastrous as any attack the ROS group could devise. Once again, let me emphasize the importance of your T-loops, since they protect your ends from errant NHEJ.

Make sure that you repair the break immediately, so that you do not push our cell into apoptosis. I cannot rest until I know that the genome is safe once again, although I am afraid I will never be able to rest as long as you two help to hold it. I am disappointed in you both.

Praescriptus

 

About the Authors

Sean Burgess is a Professor of Molecular and Cellular Biology at the University of California, Davis. She has been teaching Advanced Molecular Biology to undergraduates for 16 years.

Larissa Miyachi graduated from UC Davis in 2012. She was the recipient of the University Medal, the highest honor for a graduating senior. She is now a third year student at Stanford University School of Medicine studying anesthesiology.

, ,

Guest posts are contributed by members of our community. The views expressed in guest posts are those of the author(s) and are not necessarily endorsed by the Genetics Society of America. If you'd like to write a guest post, e-mail communications@genetics-gsa.org.

View all posts by Guest Author »

Read more in

  • Collage of 2021 Rosalind Franklin Award recipients

    Where are they now? Rosalind Franklin Young Investigator Award recipients share updates on their research

    Rosalind Franklin Young Investigator Award applications are open–make sure you submit your application or nomination of a colleague by September 30, 2024.

  • University of Minnesota researchers map genome of the last living wild horse species

    The study, published in G3: Genes|Genomes|Genetics, is part of larger conservation efforts to save Przewalski’s horse.

  • Congratulations to the Spring 2024 DeLill Nasser Awardees!

    GSA is pleased to announce the recipients of the DeLill Nasser Award for Professional Development in Genetics for Spring 2024! Given twice a year to graduate students and postdoctoral researchers, DeLill Nasser Awards support attendance at meetings and laboratory courses. The award is named in honor of DeLill Nasser, a long-time GSA supporter and National Science Foundation…

  • Carolyn Damilola headshot

    Carolyn Damilola: an NFS Rising Scientist on a lifelong quest to learn more

    Carolyn Damilola is an NFS Rising Scientist from Nigeria doing respiratory system research and paving the way for scientists from underrepresented communities through mentorship.

  • Text over a blue background image: Apply for up to $2,000 for your project from the Starter Culture Microgrant Program.

    What does a good microgrant proposal look like?

    Members of the Microgrant Review Committee share their tips for a successful proposal.

  • A blurred image of a human face is shown against a dark background.

    The first piece of the facial recognition puzzle

    New research in GENETICS gives a first peek at the molecular pathway involved in recognizing faces.

  • New Senior Editor Amy MacQueen joins GENETICS

    A new senior editor is joining GENETICS in the Genome Integrity and Transmission section. We’re excited to welcome Amy MacQueen to the editorial team.

  • Close up of an adult zebrafish with blue and white stripes in an aquarium with red lighting.

    Block party on the zebrafish sex chromosome

    Research in G3 identifies a gene regulatory block of the zebrafish genome responsible for overseeing the maternal-to-zygotic-transition.

  • Lemna Minor, the common duckweed

    Unraveling the mysteries of duckweed: epigenetic insights from Spirodela polyrhiza

    Research published in G3 offers insight into the impact of DNA methylation on clonal propagation in asexually reproducing plants.

  • Luciano Marraffini headshot

    A microbiologist’s quest to understand CRISPR in bacterial self-defense

    2024 Genetics Society of America Medal recipient Luciano Marraffini determined how CRISPR-Cas systems destroy genetic targets with precision, paving the way for gene editing technology development.

  • Elaine Ostrander headshot

    Unlocking mysteries of trait and disease heritability in dogs

    2024 Edward Novitski Prize recipient Elaine Ostrander, a pioneer of the domestic dog model, discovered numerous genes affecting dog size, morphology, behavior, and disease susceptibility—many of which have relevance in humans.

  • NSF-funded BIO-LEAPS Grant to Support Culture Change in Genetics

    GSA and collaborators Personal Genetics Education & Dialogue and Reclaiming STEM Institute launch NSF-funded BIO-LEAPS project to support culture change in genetics 

    We are thrilled to announce that the Genetics Society of America (GSA) is collaborating with the Personal Genetics Education & Dialogue (PGED) based in the Department of Genetics at Harvard Medical School, and the Reclaiming STEM Institute (RSI) on a Leading Culture Change Through Professional Societies of Biology (BIO-LEAPS) grant from the U.S. National Science…

  • Daman Saluja: Navigating Science and Policy in India

    In the Paths to Science Policy series, we talk to individuals who have a passion for science policy and are active in advocacy through their various roles and careers. The series aims to inform and guide early career scientists interested in science policy. This series is brought to you by the GSA Early Care­er Scientist…

  • Deborah Andrew headshot

    A fly geneticist’s journey into discovering rules of organ development

    2024 George W. Beadle Award recipient Deborah Andrew discovered new genes and pathways in Drosophila salivary gland organogenesis. Now, her work can help optimize cell secretion in therapeutic applications and fight malaria.

  • Małgorzata Gazda's headshot

    Małgorzata Gazda: How receiving the DeLill Nasser Award helped her land her dream job

    Have you ever experienced an event that changes the course of your life, or in this case, your career? Małgorzata (Gosia) Gazda is Assistant Professor at the University of Montreal and in 2022, she received the DeLill Nasser Award for Professional Development in Genetics, which she used to attend and present at the 2022 Population,…

  • Hongyu Zhao joins GENETICS as new Senior Editor

    A new senior editor is joining GENETICS in the Statistical Genetics and Genomics section. We’re excited to welcome Hongyu Zhao to the editorial team.

  • Julio Molina Pineda at TAGC 2024

    GSA Member Julio Molina Pineda Receives DeLill Nasser Award, Shines at TAGC 2024 

    “At any career stage, the GSA membership is an amazing investment for any genetics professional!” Julio Molina Pineda is a PhD Candidate in Cell and Molecular Biology and a Research Assistant at the University of Arkansas, and a Doctoral Academy Fellow at the Lewis Lab. In 2023, Julio was awarded the DeLill Nasser Award for…

  • Ed Grell at his dissecting microscope using ether to anesthetize his flies.

    In Memoriam: Ellsworth Herman Grell (1932–2023), a pioneer of Drosophila genome engineering and annotation

    Ellsworth (Ed) Grell blessed the Drosophila community through three enduring legacies: as a pioneer of chromosome mechanics, as a primary organizer and synthesizer of genetic knowledge in Drosophila, and as a graceful mentor to those fortunate to have known him personally. Ed grew up in rural Nebraska, completed his undergraduate studies at Iowa State, and…

  • Congratulations to the #Fungal24 Poster Award winners!

    We are pleased to announce the recipients of the GSA Poster Awards for posters presented at the 32nd Fungal Genetics Conference! Undergraduate and graduate student members of GSA were eligible for the awards, and a hard-working team of judges made the determinations. Congratulations to all! Felicia Ebot Ojong, The University of Georgia My research is focused…

  • Poster presentation tips for TAGC 2024

    You’ve been selected to present a poster at The Allied Genetics Conference 2024 in March—you’ve celebrated, made plans to attend, now what? This is an exciting opportunity to showcase your research and engage with fellow members of the genetics community, so you want to make sure you’re prepared. We wanted to offer you some tips…

  • Maximize your TAGC 2024 experience 

    A guide to all that National Harbor & DC have to offer Are you joining us for The Allied Genetics Conference 2024 in March? Make the most of your #TAGC24 experience in National Harbor! We know the science will keep you busy, but you deserve to unwind and have some fun, so we’ve curated a…

  • Early Career Leadership Spotlight: Sarah Petrosky

    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. Sarah PetroskyMultimedia SubcommitteeUniversity of Pittsburgh Research Interest I am interested in understanding adaptation that has been happening recently in populations by dissecting the ways that genes underlying an adaptation…

  • TAGC 2024 Early Career Award Winners

    GSA is pleased to announce the winners of the early career awards presented at The Allied Genetics Conference 2024. These awards are specific to particular TAGC communities and recognize early career scientists’ outstanding work on their respective research organisms. The awardees will present their talks in keynote sessions at TAGC 2024.  Don’t miss the opportunity…

  • Preeminent geneticists recognized with revamped GSA Awards

    In 2022, GSA’s Board of Directors launched an audit to review the five major awards conferred by the Society. Today, we are thrilled to announce the recipients of the reimagined GSA Awards, including the new Genetics Society of America Early Career Medal. The scientists honored this year are recognized by their peers for their outstanding…

  • Fly Board funds outreach programs to spread the word about Drosophila research

    In 2020, the Fly Board voted to use part of its reserve fund to support efforts to increase trainee participation as well as equity and diversity in the Drosophila community. An awards committee decides how the money will be spent each year, and from 2020–2022, the committee posted a very broad call for applications from…

  • New members of the GSA Board of Directors: 2024–2026

    We are pleased to announce the election of four new leaders to the GSA Board of Directors: 2024 Vice President/2025 President Brenda Andrews Professor, University of Toronto It’s an honor to continue my association with the Society by serving as Vice President of the Board of Directors. I have broad knowledge of the ongoing activities…

  • The Fly Meeting is one-of-a-kind! Dros 2025 organizers share their excitement

    The 66th Annual Drosophila Research Conference promises to be a meeting rich with the latest in Drosophila research as well as opportunities to advance your career and connect with a global community of 1,400+ scientists. The organizers Todd Nystul, Michelle Bland, Leila Rieder, Amanda Crocker, and Justin Crocker are hard at work, planning a conference…

  • Early Career Leadership Spotlight: Olufemi Osonowo

    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. Olufemi Adekunle OsonowoCareer Development SubcommitteeDalhousie University Research Interest Metabolomics and genomics are two distinct but complimentary approaches that offer valuable insights into the underlying mechanisms of complex traits, such…

  • Early Career Leadership Spotlight: Hector Mendoza

    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. Hector MendozaCommunication and Outreach SubcommitteeUniversity of Michigan Research Interest My research goals converge around the evolution of sexual reproduction. During my doctoral program, I investigated mitochondrial inheritance, a mechanism…