Faculty · Staff · Post-docs · Graduate Students

Niall G. Howlett

Research Interests

Cancer genetics, Leukemia, Breast cancer, Chromosome instability, Fanconi anemia, DNA Repair, DNA replication stress, Chromosomal fragile site stability, Homologous recombination

The study of the cellular DNA damage response is of immense importance to our health and wellbeing. Our DNA is exposed to a continual flux of intrinsic (e.g. reactive oxygen species generated during oxidative metabolism) and extrinsic (e.g. ultraviolet radiation (UV)) DNA damaging agents. How our cells respond to DNA damage defines our cancer risk, and also determines how we respond to chemo- and radiation-therapy. The importance of the cellular DNA damage response is underscored by the numerous cancer susceptibility disorders caused by mutations in DNA damage response genes, e.g. Ataxia-telangiectasia, Fanconi anemia, and Xeroderma pigmentosum. Furthermore, an impaired cellular DNA damage response is not solely associated with an elevated cancer risk: diverse clinical manifestations including various neuropathies, immune defects, mental retardation, limb and digit anomalies, and hematopoiesis defects, are often observed in these syndromes.

I am particularly interested in Fanconi anemia (FA). FA is a rare recessive disorder characterized by congenital defects, e.g. microcephaly, skin hyperpigmentation, and hand and arm anomalies, early onset hematological abnormalities, e.g. bone marrow failure and acute myeloid leukemia (AML), and solid tumors, including head, neck, esophagus, and gynecological squamous cell carcinomas (SCC). The incidence of FA is estimated to be between 1 and 3 per million live births. FA is a genetically heterogeneous disease with thirteen distinct complementation groups defined to date (A, B, C, D1/BRCA2, D2, E, F, G, I, J/BRIP1, L, M, and N/PALB2), and all thirteen of the underlying genes have been cloned or identified.

At the cellular level, the hallmark of FA is a marked sensitivity to DNA interstrand crosslinking agents, e.g. mitomycin C. DNA interstrand crosslinks represent a particularly cytotoxic lesion, preventing DNA strand separation during DNA replication and transcription. Indeed, DNA crosslinking agents are widely used, and highly effective, chemotherapeutic agents, e.g. cyclophosphamide and cisplatin. Thus, the FA pathway represents an attractive target for the chemo-sensitization of tumor cells.

Despite many recent exciting breakthroughs in FA gene identification, how the FA proteins co-operatively function in the DNA damage response, and prevent neoplastic transformation and cancer, remains to be elucidated. I am interested in addressing several important FA questions, including the following:

1. What is the in vivo physiological function of the FA pathway?
2. What is the specific DNA lesion(s) that activates the FA pathway?
3. What is the molecular basis for the increased frequency of HPV-associated tumorigenesis among FA patients?

If you are interested in joining the laboratory please email me at nhowlett@mail.uri.edu

Bibliography

1. Howlett, N.G. (2007). Fanconi anemia, breast and embryonal cancer revisited. European Journal of Human Genetics, 15, 715-717.

2. Durkin S.G., Arlt, M.F., Howlett, N.G., and Glover, T.W. (2006). Depletion of CHK1, but not CHK2, induces chromosomal instability and common fragile site breakage.  Oncogene, 25, 4381-4388.
 
3. Howlett N.G., Scuric, Z, D’Andrea, A.D., and Schiestl, R.H. (2006). Impaired DNA double strand break repair in cells from Nijmegen Breakage Syndrome patients.  DNA Repair, 5, 251-257.

4. Howlett N.G., Taniguchi, T., Durkin S.G., D’Andrea, A.D., and Glover, T.W. (2005).  The Fanconi anemia pathway is required for the DNA replication stress response and the regulation of common fragile site stability.  Human Molecular Genetics, 14, 693-701.

5. Secretan M.B., Scuric Z., Oshima J., Bishop A.J., Howlett N.G., Yau D., Schiestl R.H. (2004).  Effect of Ku86 and DNA-PKcs deficiency on non-homologous end-joining and homologous recombination using a transient transfection assay.  Mutation Research, 554, 351-364.

6. Egorov A.I., Howlett N.G., Schiestl R.H. (2004).  Mutagen X and chlorinated tap water are recombinagenic in yeast.  Mutation Research, 563, 159-169.

7. Howlett, N.G. and Schiestl, R.H. (2004).  Nucleotide excision repair deficiency causes elevated levels of chromosome gain in Saccharomyces cerevisiae. DNA Repair, 3, 127-134.

8. Liu, T.X., Howlett, N.G., Deng, M., Langenau, D.M., Hsu, K., Rhodes, J., Kanki, J.P., D’Andrea, A.D., and Look, T.A. (2003).  Disruption of zebrafish fancd2 causes developmental abnormalities via p53-dependent apoptosis. Developmental Cell, 5, 903-914.

9. Vonarx, E.J., Howlett, N.G., Schiestl, R.H., and Kunz, B.A. (2002).  Detection of Arabidopsis thaliana AtRAD1 cDNA variants and assessment of function by expression in a yeast rad1 mutant.  Gene, 296, 1-9.

10. Howlett, N.G., Taniguchi, T., Olson, S., Cox, B., Waisfisz, Q., de Die-Smulders, C., Persky, N., Grompe, M., Joenje, H., Pals, G., Ikeda, H., Fox, E.A., and D’Andrea, A.D. (2002).  Biallelic inactivation of BRCA2 in Fanconi Anemia.  Science, 297, 606-609.

11. Howlett, N.G. and Schiestl, R.H. (2000).  Simultaneous measurement of the frequencies of homologous recombination and chromosome gain using the yeast DEL assay.  Mutation Research, 454, 53-62.

12. Howlett, N.G. and Avery, S.V. (1999).  Flow cytometric investigation of heterogeneous copper-sensitivity in asynchronously grown Saccharomyces cerevisiae.  FEMS Microbiology Letters, 176, 379-386.

13. Howlett, N.G. and Avery, S.V. (1997).  Induction of lipid peroxidation during heavy metal stress in Saccharomyces cerevisiae and influence of plasma membrane fatty acid unsaturation.  Applied and Environmental Microbiology, 63, 2971-2976.

14. Howlett, N.G. and Avery, S.V. (1997).  Relationship between cadmium sensitivity and degree of plasma membrane fatty acid unsaturation in Saccharomyces cerevisiae.  Applied Microbial Biotechnology, 48, 539-545.

15. Avery, S.V., Howlett, N.G. and Radice, S. (1996).  Copper toxicity towards Saccharomyces cerevisiae: Dependence on plasma membrane fatty acid composition.  Applied and Environmental Microbiology, 62, 3960-3966.