Niall G. Howlett, Ph.D.

Research Website

Biography

Dr. Niall G. Howlett (or Niall) received his PhD from Oxford Brookes University in the UK in 1999 and performed postdoctoral research at Harvard School of Public Health, the Dana-Farber Cancer Institute, and the University of Michigan. He joined the University of Rhode Island as an Assistant Professor in the Department of Cell and Molecular Biology in 2007. Dr. Howlett’s research program is focused on the eukaryotic DNA damage response and the etiology of hereditary cancer susceptibility syndromes associated with defective DNA repair, with a particular focus on the molecular pathogenesis of Fanconi anemia (FA). FA is a rare genetic disease characterized by congenital defects, increased risk for bone marrow failure (BMF) and cancer, and premature mortality. Dr. Howlett has made numerous important contributions to the field of FA research culminating in several high impact publications, including publications in Science, Molecular Cell, Blood, and Nucleic Acids Research. Over the course of his independent faculty position at the University of Rhode Island he has mentored over 40 trainees including postdoctoral research fellows, graduate students, and undergraduate students. The Howlett laboratory has received funding from multiple federal and private sources including the NIH, the Department of Defense (DoD), the Leukemia Research Foundation, and the Fanconi Anemia Research Fund. Dr. Howlett is currently the PI of the URI MARC U*STAR program, an NIH-funded T34 undergraduate research training program for students from historically underrepresented populations. He previously served as the program coordinator of the RI-INBRE program.   

Research

Fanconi Anemia and the Cellular DNA Damage Response
Fanconi anemia (FA) is a rare genetic disease characterized by developmental defects, progressive bone marrow failure, and increased susceptibility to cancer. The incidence of FA is estimated to be between 1 in 200,000-400,000 live births. To date, 15 FA genes have been identified: FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG/XRCC9, FANCI, FANCJ/BRIP1, FANCL, FANCM, FANCN/PALB2, FANCO/RAD51C, and FANCP/SLX4. The protein products of these genes are thought to act cooperatively in a pathway, the FA-BRCA pathway, to repair DNA damage and prevent cellular transformation. The study of FA is highly significant for several reasons. First and foremost, FA is a devastating and life-threatening disease that affects several hundred US families alone. Therapeutic options for FA are extremely limited. A greater understanding of the molecular basis of FA will ultimately lead to improved diagnostic and therapeutic approaches to FA, directly benefiting FA patients and their families. Second, as FA is unequivocally linked to both hematologic and non-hematologic cancer susceptibility, our findings will provide important mechanistic insight in to the molecular origins of cancer susceptibility in the general (non-FA) population.

Regulation of the Mono-Ubiquitination of the FANCD2 and FANCI proteins
A central step in the regulation of the activation of the FA-BRCA pathway is the mono-ubiquitination of the FANCD2 (and FANCI) proteins. How this important post-translational modification step is regulated is poorly understood. Furthermore, the role of mono-ubiquitinated FANCD2 in the DNA damage response is unknown. We use biochemical and genetic methods to address these two important questions in FA biology.

Understanding the Role of the FA-BRCA Pathway in the Suppression of Genomic Copy Number Variation
Copy number variation, or copy number change, which refers to deletions or duplications of tens of thousands to millions of nucleotides, is both a normal feature of genetic variation and a major contributor to genetic disease. The mechanisms by which copy number change occurs and the cellular pathways that suppress copy number change are largely unknown. We have recently uncovered an important role for the FA-BRCA pathway in the suppression of de novo copy number change, and are using multiple approaches to further characterize this function.

Education

  • Research Fellow in Pediatric Oncology, Dana-Farber Cancer Institute (Boston, MA), 2001-2003
  • Research Fellow in Cancer Cell Biology, Harvard School of Public Health, 1998-2001
  • Ph.D., Biological and Molecular Sciences, Oxford Brookes University (Oxford, U.K.), 1999
  • B.Sc., Industrial Biochemistry, University of Limerick (Limerick, Ireland), 1994

Selected Publications

Rego, M.A., Harney, J.A., Mauro, M., Shen, M., and Howlett, N.G. (2011). Regulation of the activation of the Fanconi anemia pathway by the p21 cyclin-dependent kinase inhibitor. Oncogene, in press.

Cybulski, K.E., and Howlett, N.G. (2011). FANCP/SLX4: A Swiss army knife of DNA interstrand crosslink repair. Cell Cycle, 10, Epub ahead of print.

Hicks J.K., Chute C.L., Paulsen M.T., Ragland R.L., Howlett N.G., Guéranger Q., Glover T.W., and Canman C.E. (2010). Differential roles for DNA polymerases Eta, Zeta, and REV1 in lesion bypass of intrastrand versus interstrand DNA cross-links. Molecular and Cellular Biology, 30, 1217-1230.

Howlett, N.G., Harney J.A., Rego, M.A., Kolling IV, F.W., and Glover, T.W. (2009). Functional interaction between the Fanconi anemia D2 protein PCNA via a conserved PCNA-interaction motif. Journal of Biological Chemistry, 284, 28935-28942.

Rego, M.A., Kolling, F.W., and Howlett, N.G. (2009). The Fanconi Anemia Protein Interaction Network: Casting a Wide Net. Mutation Research, 668, 27-41.

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

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.

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.

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.

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.

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.

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.

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.