Alexander J. R. Bishop, D.Phil
Our research focus
“My lab focuses on DNA damage response and DNA repair, with a particular interest in Ewing sarcoma, breast cancer, and Ataxia telangiectasia. My lab uses various methods; genetics, molecular biology, cell biology, and mouse models (genetic and tumor models). Of my 50+ peer-reviewed publications, half are on DNA repair, particularly homologous recombination. Over the last 20 years, I expanded my research program to use genomic level approaches to facilitate my research interests, from microarray analyses to genome-wide RNAi screening and then many genomic sequencing technologies. We have also developed significant expertise in R-loops biology and how it relates to DNA repair and replication. Importantly we established key techniques to evaluate R-loops, including DRIPseq and RNAPII ChIPseq. The relationship between these various endeavors and expertise is most apparent in the work we published about a year ago (Nature 2018) outlining the transcriptional dysregulation in Ewing sarcoma, another recently published paper where we contributed the R-loop analyses for ETMR (Nature, 2019). Another collaborative project examining R-loops in rDNA and how they function to maintain phase separation of nucleolar bodies (and how they are disrupted in Ewing sarcoma) was just accepted for publication at Nature (2020).
I have a particular interest in the ATM/p53/BRCA1 damage response pathway and how it relates to the control of homologous recombination and cancers. Towards this end, we have a tremendous set of resources to evaluate DNA repair and damage responses, expertise in RNAi, gene expression, ChIP, protein interactions, transcription stress, bioinformatics, and some metabolomics to apply to this problem. We have also developed an expertise in NRF2 biology and demonstrated how this pathway is key for preventing unfolded protein response induced cell death in response to alkylation damage.
Since becoming an independent investigator, I have trained six postdoctoral fellows, all of whom remained in science, four of whom are continuing their academic careers, two now tenured, and one is currently a non-tenure track Assistant Professor. One postdoc is pursuing additional training while yet another joined a biotech company. Two additional postdoctoral fellows are currently under training. I have taken a special interest in advancing postdoctoral fellows through their careers. Since coming to UT Health –San Antonio, I have developed a postdoctoral career workshop. I am a member of a Departmental Committee to promote postdoctoral career advancement and, most recently, initiated a Departmental Postdoctoral Seminar Series. Therefore, I am a strong advocate for finding means for postdoctoral fellows to achieve their career goals.
I have also been fortunate enough to have recruited several talented graduate students, six have now graduated, and all pursued further research careers in either academia or private industry. I am currently training four graduate students. Over the last few years, two of my graduate students and two of my postdocs benefited from this CPRIT training grant. In contrast, four of my graduate students obtained independent funding (including the DoD BRCP program and PCRCP Horizon Award), as did three of my postdocs (including DoD BCRP and AstraZeneca-AACR START). I am therefore wholly committed to being a co-Investigator for this CPRIT training grant, thus facilitating training young scientists and seeing them succeed in their careers.”
Learn more about the Bishop Lab from their external site.
- Homologous Recombination Repair – DNA repair by homologous recombination
- DNA Damage Response – DNA damage, survival, signaling (particularly ATM-p53 pathway), transcriptional stress and R-loop detection and replication stress (DNA combing and ATR signaling pathway)
- Systems Biology – RNAi screening, gene expression analyses, protein interactome, comparative biology and metabolomics, and metabolic flux
- Cancer biology – Ewing Sarcoma and Breast Cancer
- Ataxia Telangiectasia and Bloom Syndrome
Traveling the road of childhood cancer, from cause to cure
Ewing sarcoma– a bone/tissue sarcoma
Ewing sarcoma usually displays exquisite sensitivity to a variety of damaging agents (chemotherapies), but the reason for this damage response defect is not known. Our work identified that these sarcomas lack most of the normal damage responses because of an RNA metabolism issue that traps the BRCA1 protein, the gene usually associated with breast cancer. The unavailability of BRCA1 leads to a DNA repair defect that can be specifically targeted in the treatment of these cancers.
Ataxia-telangiectasia (AT) is caused by a mutation in ATM, a key damage response gene. AT patients suffer from immune dysfunction, neurological defects, as well as cancer and diabetes predisposition. Aside from understanding that AT cells are sensitive to irradiation, little is understood about the clinical manifestation of the disease. To develop new insights we have examined the diabetes development associated with this disease and discovered that ß-cells have a metabolic problem resulting from a defect in importing cysteine; this defect results in an accumulation of glutamate and a defect in respiration. These observations provide new insight into disease development. Further, we have been able to demonstrate that we can rescue the diabetes phenotype by circumventing the cysteine import defect. We are now exploring the impact of this defect and intervention on the neurological defect and cancer development in AT.
Homologous recombination defective diseases
Homologous recombination defective diseases combination is associated with BRCA1 and BRCA2, the breast, and ovarian cancer-predisposing genes. We are particularly interested in mechanisms that control homologous recombination. Towards this, we study proteins such as BLM, p53, 53BP1, ATR, and CREBBP. When the genes of these proteins are inherited in a mutated for they lead to diseases usually associated with early-onset cancer; Bloom syndrome, Li Fraumeni, Seckel syndrome, and Myelodysplastic syndrome. Using mouse and cell models we work to examine these diseases, their impact on homologous recombination, and the molecular basis of these interactions. We have already discovered new roles for some of these proteins. For example, 53BP1 mutation occurs in chemorefractory BRCA1 breast cancers and Ewing’s sarcoma. However, we have found that loss of 53BP1 also results in DNA replication stress and this provides a new avenue for treating those cancers that have acquired these mutations. It is exactly this type of novel insight that expects will lead to better, more targeted therapies and preventative measures. Because of the interactions with homologous recombination and BRCA1/BRCA2 proteins, our work also impacts adult cancers, particularly breast and ovarian cancers. More importantly, because of these relationships, we hope to take advantage of the discoveries for targeted therapies developed in adult cancers to apply to childhood cancers.
Current Lab Members
Nicklas Bassani, PhD
Graduate Research Assistant
Rotation Student Mays Cancer Center Predoctoral Fellowship
Graduate Research Assistant
Graduate Research Assistant
2020 Greehey Fellowship
CPRIT 2020 Predoctoral Training Fellowship
Former Lab Members
Lindsey Barron PhD, Student Xavier Bernanrd Postdoctoral Student, Adam Brown PhD Student, Ana Chavez-Santoscoy PhD Student, Ravi Dashnamoorthy Postdoctoral Student, Aparna Gorthi, Postdoctoral Fellow, Bijal Karia PhD Student, Manish Parihar, PhD Research Scientist, Sonal Tonapi PhD Student, Subapriya Rajamanickam Postdoctoral Student, Carolina Romero Sandoval Postdoctoral Fellow, Erin Sybouts PhD Student, Postdoctoral Student, Amy Wiles Postdoctoral Student, Alfeu Zanotto-Filho Postdoctoral Student
- The Gear Up Against Kids Cancer Rides Again! January 20, 2023
- Computers in Biology and Medicine: Omics-based identification of an NRF2-related auranofin resistance signature in cancer: Insights into drug repurposing (Bishop Lab) December 12, 2022
- NPJ | Precision Oncology: An international working group consensus report for the prioritization of molecular biomarkers for Ewing sarcoma (Bishop) September 21, 2022