Education:
BS 1984 Chemistry - University of Bologna, Italy
PhD 1990 Biochemistry - University of California, Davis, CA
Postdoctoral Research Fellowship:
1991 - 1994 University of California, Berkeley
Started at USC: 1995
Research Topics: Cancer Cell Biology, Cell Cycle, Growth & Proliferation, Aging, Gene Regulation/Transcription, DNA Replication, Repair, Modification
Research Description
The research in our laboratory focuses on the following topics:
1. The Werner syndrome protein in DNA damage and genomic stability;
2. Lamin A mutations in Hutchinson-Gilford Progeria syndrome;
3. Mechanisms of transcriptional regulation.
We study the role that the Werner syndrome protein plays in genome stability and in the progression of aging-related diseases such as cancer and cardiovascular disease. 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.
We study the molecular basis of the accelerated aging and cardiovascular disease caused by the synthesis of an abnormal lamin A protein (progerin) in Hutchinson-Gilford progeria syndrome (HGPS) patients. 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.
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 RNA polymerase I transcription. 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 DNA genes. We are currently studying how posttranslational modifications such as phosphorylation and acetylation influence the assembly of the transcriptional machinery on the rDNA promoter. In parallel studies, we are working on the identification of the cellular factors responsible for these modifications.
10 Selected Publications:
Click here to view all the publications for this faculty
Dansithong W,Wolf CM,Sarkar P,Paul S,Chiang A,Holt I,Morris GE,Branco D,Sherwood MC,Comai L,Berul CI,Reddy S - Cytoplasmic CUG RNA foci are insufficient to elicit key DM1 features. - PLoS ONE [2008] ;3(12):e3968 PubMed
Candelario J,Sudhakar S,Navarro S,Reddy S,Comai L - Perturbation of wild-type lamin A metabolism results in a progeroid phenotype. - Aging Cell [2008] Jun;7(3):355-67 PubMed
Li B,Jog SP,Reddy S,Comai L - WRN controls formation of extrachromosomal telomeric circles and is required for TRF2DeltaB-mediated telomere shortening. - Mol Cell Biol [2008] Mar;28():1892-904 PubMed
Madia F,Gattazzo C,Wei M,Fabrizio P,Burhans WC,Weinberger M,Galbani A,Smith JR,Nguyen C,Huey S,Comai L,Longo VD - Longevity mutation in SCH9 prevents recombination errors and premature genomic instability in a Werner/Bloom model system. - J Cell Biol [2008] Jan 14;180():67-81 PubMed
Lin CH,Platt MD,Ficarro SB,Hoofnagle MH,Shabanowitz J,Comai L,Hunt DF,Owens GK - Mass spectrometric identification of phosphorylation sites of rRNA transcription factor upstream binding factor. - Am J Physiol Cell Physiol [2007] May;292(5):C1617-24 PubMed
Lin CY,Navarro S,Reddy S,Comai L - CK2-mediated stimulation of Pol I transcription by stabilization of UBF-SL1 interaction. - Nucleic Acids Res [2006] ;34(17):4752-66 PubMed
Paul S,Dansithong W,Kim D,Rossi J,Webster NJ,Comai L,Reddy S - Interaction of muscleblind, CUG-BP1 and hnRNP H proteins in DM1-associated aberrant IR splicing. - EMBO J [2006] Sep 20;25(18):4271-83 PubMed
Sheng Z,Liang Y,Lin CY,Comai L,Chirico WJ - Direct regulation of rRNA transcription by fibroblast growth factor 2. - Mol Cell Biol [2005] Nov;25():9419-26 PubMed
Zhang C,Comai L,Johnson DL - PTEN represses RNA Polymerase I transcription by disrupting the SL1 complex. - Mol Cell Biol [2005] Aug;25():6899-911 PubMed
Banerjee R,Weidman MK,Navarro S,Comai L,Dasgupta A - Modifications of both selectivity factor and upstream binding factor contribute to poliovirus-mediated inhibition of RNA polymerase I transcription. - J Gen Virol [2005] Aug;86():2315-22 PubMed
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