Educational Background: Dr. Comai received his Ph.D.in Biochemistry in 1990 from the University of California, Davis and completed his postdoctoral training at University of California, Berkeley. He joined the faculty of the Keck School of Medicine in 1995 and became a member of the Institute for Genetic Medicine in 2005.

RESEARCH INTERESTS

The research in my laboratory focuses on the molecular basis of human aging. We study the cellular processes leading to the development of Werner syndrome (WS) and Hutchinson-Gilford Progeria syndrome (HGPS), two premature aging diseases. In addition, we study the mechanisms of nucleolar gene transcription and replication and their relationship to human aging.

1. The role of the Werner syndrome protein in DNA damage and genome stability;
Werner Syndrome is an adult form of progeria that is characterized clinically by the premature appearance of cataracts, diabetes mellitus, neoplasia and atherosclerosis. The most common cause of death in WS individuals is myocardial infarction at the median age of 45 years. At the molecular level, cells from WS patients display a high degree of chromosomal deletions and rearrangements. The Werner syndrome protein (WRN) is a nucleolar protein with exonuclease and helicase activities whose cellular function remains unknown. Our studies have revealed a functional relationship between WRN and Ku70/80, a complex that is involved in the non-homologous end joining (NHEJ) DNA repair pathway and in telomere maintenance. These findings suggest that the Werner syndrome protein may be involved in the repair of DNA breaks at specific chromosomal locations, and we are using biochemical approaches to test this hypothesis.

2. Functional analysis of lamin A mutations causing Hutchinson-Gilford Progeria syndrome.
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by premature senescence. Affected children appear normal at birth, but within a year develop characteristic features of old age. The majority of HGPS children die from cardiac disease at an average age of 13 years. Genetic studies have identified a mutation in the lamin A/C gene in 18 classical HGPS cases. The mutation results in the production of a mutant lamin A protein with an internal deletion termed progerin. The mechanism by which expression of progerin leads to accelerated aging and cardiovascular disease is unknown. Lamin A is thought to be required for the maintenance of the nuclear structure and it has been proposed to influence nuclear processes such as gene transcription and DNA replication possibly through interaction with a set of yet to be identified cellular factors. We hypothesize that expression of the mutant HGPS lamin A protein results in premature aging and cardiac disease as a consequence of the altered composition and function of lamin A-containing complexes within the nucleus. Current studies use biochemical and genetic approaches to study the cellular defects associated with progerin expression.

3. Mechanisms of regulation of nucleolar gene expression and DNA replication.
We study the mechanisms that regulate gene expression in mammalian cells and the long-term goal of this project is to define the link between the signals that control cell growth and transcription of ribosomal RNA genes. Recent work from our laboratory has indicated that modification of one or more transcription factors controls the assembly of the preinitiation complex and efficient transcription of the ribosomal RNA genes. We are currently studying how posttranslational modifications influence the assembly of the transcriptional machinery on the rRNA gene promoter. In parallel studies, we are working on the identification of the cellular factors responsible for these modifications. Lastly, we are interested in dissecting the processes involved in the unidirectional DNA replication of rDNA gene arrays.

Selected Publications:

Dansithong W, Paul S, Comai L, Reddy S. MBNL1 is the primary determinant of focus formation and aberrant insulin receptor splicing in DM1. J Biol Chem [ 2005 ] Feb 18;280(7):5773-80 .

Comai L, Li B. The Werner syndrome protein at the crossroads of DNA repair and apoptosis. Mech Ageing Dev [ 2004 ] Aug;125(8):521-8 .

Comai L. Mechanism of RNA polymerase I transcription. Adv Protein Chem [ 2004 ] 67:123-55 .

Li B, Navarro S, Kasahara N, Comai L. Identification and biochemical characterization of a Werner's syndrome protein complex with Ku70/80 and poly(ADP-ribose) polymerase-1. J Biol Chem [ 2004 ] Apr 2;279(14):13659-67. .
Lin CY, Tuan J, Scalia P, Bui T, Comai L. The cell cycle regulatory factor TAF1 stimulates ribosomal DNA transcription by binding to the activator UBF. Curr Biol [ 2002 ] Dec 23;12(24):2142-6 .

Li B, Comai L. Displacement of DNA-PKcs from DNA ends by the Werner syndrome protein. Nucleic Acids Res [ 2002 ] Sep 1;30(17):3653-61 .

Scalia P, Heart E, Comai L, Vigneri R, Sung CK. Regulation of the Akt/Glycogen synthase kinase-3 axis by insulin-like growth factor-II via activation of the human insulin receptor isoform-A. - J Cell Biochem [ 2001 ] 82(4):610-8 .

Li B, Comai L. Requirements for the nucleolytic processing of DNA ends by the Werner syndrome protein-Ku70/80complex. J Biol Chem [ 2001 ] Mar 30;276(13):9896-902 .

Dr. Lucio Comai's complete publication