Bishop Lab

Alexander J.R. Bishop, D.Phil

Bishop Lab

Rank: Associate Professor
Department: Cell Systems & Anatomy
Programmatic Member: Molecular Medicine
Office: 3.100.14
Tel: 210.562.9060
Email: bishopa@uthscsa.edu

The interest of our lab is to identify and understand the mechanisms of damage survival. People who inherit a deficiency in damage response are predisposed to develop cancer, usually as children or young adolescents. Further, most cancer treatments are based on damaging cancer cells, so understanding why a chemotherapy works, and for which patients, should lead to more effective and less toxic treatments that will increase the cure rate and improve quality of life for cancer survivors.

Lab Research

Expertise

  • Homologous Recombination Repair – DNA repair by homologous recombination
  • Systems biology – RNAi screening, protein interactome, and comparative biology

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

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 a 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.

Lab Staff

Nicklas Bassani, Ph.D.
Postdoctoral Fellow

Angela Jasper
Rotation Student

Kevin Kanda
Rotation Student

Liesl Lawrence
Graduate Research Assistant

Eva Loranc
Research Assistant

Henry Miller
Graduate Research Assistant

Pramiti Mukhopadhyay
Rotation Student

Carolina Romero Sandoval
Postdoctoral Fellow

Erin Sybouts
Graduate Research Assistant