Research Abstract:
Alterations of nuclear architecture, chromatin structure and telomere biology are associated with aging and cancer. The research in our laboratory focuses on understanding the functional interplay between these processes. Our ultimate goal is to identify molecular pathways that can be targeted in cancer therapy as well as in the amelioration of aging-related phenotypes.
Epigenetic alterations, mainly in DNA methylation and modification of histones, are recognized as mechanisms contributing to malignancy. One of the aims of our research is the characterization of epigenetic mechanisms that regulate chromatin structure and the impact that epigenetic alterations have on chromosome stability, tumorigenesis and radiosensitivity.
Our specific goals are: (1) Characterize novel mechanisms regulating telomere chromatin structure and function in mammalian cells. A number of chromatin-modifying activities have been identified that participate in the acquisition of a heterochromatic structure at mouse telomeres. Abrogation of the different activities leads to telomere length deregulation. Given that telomere homeostasis is essential for genomic stability and regulation of cellular proliferative potential, it is of crucial importance to identify mechanisms regulating telomeric function as well as their contribution to the development and progression of tumoral processes. (2) Evaluate the impact of chromatin alterations on the DNA damage response pathway. Recent evidence supports a role for chromatin-modifying activities in the DNA damage response. In addition, chromatin alterations that disrupt telomere function might trigger telomere-damage induced activation of the DNA damage response pathway. By comparing ionizing radiation sensitivity and activation of a DNA damage response between epigenetically normal and altered cells, we are investigating the implication of different chromatin modifications on DNA repair.
Alterations of nuclear architecture affect nuclear function. In particular, mutations in the LMNA gene encoding the nuclear proteins A-type lamins lead to a variety of changes of nuclear structure and chromatin modifications. These changes are accompanied by defects in DNA replication and repair as well as gene transcription and silencing. LMNA gene mutations have been associated with degenerative disorders broadly termed laminopathies. Hutchison Gilford Progeria Syndrome is the most devastating lamin-related disease, with kids exhibiting phenotypes of premature aging and dying at adolescence from severe cardiovascular complications. In addition, changes in the expression of A-type lamins are emerging as a factor contributing to tumorigenesis. Given that increased genomic instability is a hallmark of cancer and aging, we have undertaken the characterization of the effect that disease-causing alterations of A-type lamins function has on genomic stability. Specifically, our studies aim to determine how alterations of A-type lamins impact on the maintenance of telomere structure, length and function as well as on the DNA damage response pathway and DNA repair mechanisms.
Selected Publications:
Gonzalez-Suarez I*, Redwood AB*, Perkins SM, Vermolen B, Lichtensztejin D, Grotsky DA, Morgado-Palacin L, Gapud E, Sleckman BP, Sullivan T, Sage J, Stewart CL, Mai S and Gonzalo S. Novel roles for A-type lamins on telomere biology and the DNA damage response pathway. EMBO J. 2009 Aug 19;28(16):2414-27. *Contributed equally to this work.
Zeng S, Xiang T, Pandita TK, Gonzalez-Suarez I, Gonzalo S, Harris CC and Yang Q. Telomere recombination requires the MUS81 endonuclease. Nat. Cell Biol. 2009 May 11(5): 616-23.
Gonzalez-Suarez I and Gonzalo S. Crosstalk between chromatin structure, nuclear compartmentalization, and telomere biology. Cytogenet Genome Res 2008 122:202-210. Review.
Gonzalo S, Jaco I, Fraga MF, Chen T, Li E, Esteller M, and Blasco MA. DNA methyltransferases control telomere length and telomere recombination in mammalian cells. Nat. Cell Biol. 2006 April 8(4): 416-24.
Gonzalo S*, García-Cao M*, Fraga MF, Schotta G, Peters AHFM, Cotter S, Eguía R, Dean DC, Esteller M, Jenuwein T, and Blasco MA. Role of Rb family in stabilizing histone methylation at constitutive heterochromatin. Nat. Cell Biol. 2005 April 7(4): 420-8. *Contributed equally to this work.
Last Updated: 08/31/2009 |