Dr. Niall Howlett's Lab

Department of Cell and Molecular Biology - College of the Environment and Life Sciences

Team FARF pictured after the 2016 Pell Bridge Run, a 4 mile run/walk across the Claiborne Pell Bridge from Jamestown to Newport, R.I. Team FARF 2016 included the Fiaschetti, Eminger, and Mackowicz families and friends as well as members of the Howlett lab.

The Howlett Lab is located in the Department of Cell and Molecular Biology at the University of Rhode Island. We are studying the eukaryotic cellular DNA damage response and, in particular, the molecular pathogenesis of the rare genetic disease Fanconi anemia.

Fanconi anemia is clinically characterized by congenital malformations, progressive bone marrow failure, increased cancer susceptibility, and premature mortality. FA is both autosomal and X-linked (FA complementation group B is caused by mutation in the X-linked FANCB gene). The incidence of FA in the U.S. is approximately 1 in 120,000 live births. There are currently twenty one defined FA complementation groups (A, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q, R, S, T, U, and V) and all twenty one underlying genes (FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ/BRIP1, FANCL, FANCM, FANCN/PALB2, FANCO/RAD51C, FANCP/SLX4, FANCQ/ERCC4, FANCR/RAD51, FANCS/BRCA1, FANCT/UBE2T, FANCU/XRCC2, and FANCV/REV7) have been identified. However, several unassigned FA complementation groups exist, and new FA genes remain to be discovered.

At the cellular level, FA is characterized by elevated chromosome instability and hypersensitivity to DNA interstrand crosslinking agents, e.g. cisplatin and mitomycin C, and reactive aldehydes, e.g. acetaldehyde and formaldehyde. The FA proteins, together with the protein products of the two major breast cancer susceptibility genes BRCA1 and BRCA2, function cooperatively in the FA-BRCA pathway to repair DNA damage and to prevent cancer. The FA proteins also play an essential role in the maintenance of genome stability during the process of DNA replication. Importantly, the regulation of the FA-BRCA pathway and its function(s) in cellular DNA repair and replication processes remain poorly understood. A greater understanding of these processes will ultimately lead to improved diagnostic and therapeutic approaches to FA.
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