Education
Ph.D., Washington University School of Medicine
Research Interests
The human genome is organized into different levels of complexity. Packaging of DNA into different chromatin states and 3D nuclear organization of the genome are emerging as additional levels of regulation of genome function. Our broad research interests are to understand how alterations of nuclear architecture, chromatin structure, and genome stability contribute to the processes of aging and cancer. Our studies revealed that the structural nuclear proteins A-type lamins play a key role in the maintenance of telomere structure, length and function, as well as mechanisms of DNA double-strand break repair. Specifically, loss of A-type lamins increases the levels of the protease cathepsin L and its entry into the nucleus, which in turn leads to degradation of proteins with important roles in cell cycle regulation -Rb family members- and DNA repair -53BP1-. Loss of A-type lamins also leads to repression of BRCA1 and RAD51 genes, critical factors in homologous recombination. Interestingly, inhibition of cathepsin L activity with vitamin D or specific inhibitors rescues some of the phenotypes of lamins-deficient cells, providing new therapeutic possibilities. Most recently, we found that these novel pathways are also activated in BRCA1-deficient cells and subsets of breast cancer patients. Our current work aims to characterize in detail how these pathways contribute to the pathophysiology of cancer, aging, and laminopathies with the ultimate goal of using them as potential biomarkers for diagnosis, prognosis, and customization of treatment.
Recent Publications
  • Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations.
    Gonzalo S, Kreienkamp R, Askjaer P. Ageing Res Rev. (2016) Jun 29 [Epub ahead of print].
  • The nuclear lamina in health and disease.
    Dobrzynski A, Gonzalo S, et al. Nucleus. (2016) 7(3):233-248.
  • Methods to monitor DNA repair defects and genomic instability in the context of a disrupted nuclear lamina.
    Gonzalo S, Kreienkamp R. Methods Mol Biol. (2016) 1411:419-437.
  • Vitamin D receptor signaling improves Hutchinson-Gilford progeria syndrome cellular phenotypes.
    Kreienkamp R, Croke M, et al. Oncotarget. (2016) Apr 27 [Epub ahead of print].
  • Vitamin D/vitamin D receptor axis regulates DNA repair during oncogene-induced senescence.
    Graziano S, Johnston R, et al. Oncogene. (2016) Apr 4 [Epub ahead of print].
  • Tying up loose ends: telomeres, genomic instability and lamins.
    Gonzalo S, Eissenberg JC. Curr Op Genet Dev. (2016) 37:109-118.
  • Loss of lamin A function increases chromatin dynamics in the nuclear interior.
    Bronshtein I, Kepten E, et al. Nat Commun. (2015) 6:8044-8052.
  • DNA repair defects and genome instability in Hutchinson-Gilford Progeria Syndrome.
    Gonzalo S, Kreienkamp R. Curr Opin Cell Biol. (2015) 34:75-83.
Significant Publications as an Independent Investigator

BRCA1 loss activates cathepsin L-mediated degradation of 53BP1 in breast cancer cells.


David A. Grotsky, Ignacio Gonzalez-Suarez, Anna Novell, Martin A. Neumann, Sree C. Yaddanapudi, Monica Croke, Montserrat Martinez-Alonso, Abena B. Redwood, Sylvia Ortega-Martinez, Zhihui Feng, Enrique Lerma, Teresa Ramon y Cajal, Junran Zhang, Xavier Matias-Guiu, Adriana Dusso, and Susana Gonzalo.


J. Cell Biol. 200(2):187-202, 2013 (PMID 23337117)

Breast cancers classified as triple-negative (TNBC) and BRCA1-deficient are particularly aggressive and difficult to treat. A major breakthrough was the finding that these tumors are exquisitely sensitive to inhibitors of poly(ADP-ribose) polymerase (PARPi). Phase II clinical trials have shown encouraging outcomes with tolerable side effects. However, a significant fraction of these cancers acquire resistance. Elegant studies demonstrated that loss of the DNA repair protein 53BP1 contributes to the resistance of BRCA1-deficient cells and tumors to PARPi. Thus, raising the levels of 53BP1 in these aggressive tumors could potentially restore their sensitivity to PARPi and other genotoxic agents.

In this study, we uncovered a molecular mechanism regulating 53BP1 levels that can be targeted for therapeutic purposes. We demonstrated that BRCA1 loss activates cathepsin L (CTSL)–mediated degradation of 53BP1, rescuing homologous recombination repair and allowing BRCA1-deficient cells to overcome genomic instability and growth arrest. Importantly, depletion or inhibition of CTSL with vitamin D or specific inhibitors stabilized 53BP1 and increased genomic instability in response to radiation and PARPi, compromising proliferation. Analysis of human breast tumors identified nuclear CTSL as a positive biomarker for TNBC, which correlated inversely with 53BP1. Importantly, nuclear levels of CTSL, vitamin D receptor (VDR), and 53BP1 emerged from this study as a novel triple biomarker signature for stratification of patients with BRCA1-mutated tumors and TNBC, with potential predictive value for drug response. We identified here a novel pathway with prospective relevance for diagnosis and customization of breast cancer therapy.

Model of functional relationship between vitamin D/VDR axis and DNA repair factors during Ras-induced senescence.




Vitamin D/vitamin D receptor axis regulates DNA repair during oncogene-induced senescence.


Simona Graziano, Rachel Johnston, O. Deng, Junran Zhang, and Susana Gonzalo.


Oncogene. Apr 4 [Epub ahead of print], 2016. (PMID 27041576)

Oncogenic Ras expression is associated with activation of the DNA damage response (DDR) pathway, as evidenced by elevated DNA damage, primarily DNA double-strand breaks (DSBs), and activation of DNA damage checkpoints, which in primary human cells leads to entry into senescence. DDR activation is viewed as a physiological barrier against uncontrolled proliferation in oncogenic Ras-expressing cells, and arises in response to genotoxic stress due to the production of reactive oxygen species (ROS) that damage DNA, and to hyper-replication stress. Although oncogene-induced senescence (OIS) is considered a tumor suppressor mechanism, the accumulation of DNA damage in senescent cells is thought to cause genomic instability, eventually allowing secondary hits in the genome that promote tumorigenesis. To date, the molecular mechanisms behind DNA repair defects during OIS remain poorly understood.

Our study shows that oncogenic Ras expression in human primary cells results in down-regulation of BRCA1 and 53BP1, two key factors in DNA DSBs repair by homologous recombination (HR) and non-homologous end joining (NHEJ), respectively. As a consequence, Ras-induced senescent cells are hindered in their ability to recruit BRCA1 and 53BP1 to DNA damage sites. While BRCA1 is down-regulated at transcripts levels, 53BP1 loss is caused by activation of cathepsin L (CTSL)-mediated degradation of 53BP1 protein. Moreover, we discovered a marked down-regulation of vitamin D receptor (VDR) during OIS, and a role for the vitamin D/VDR axis regulating the levels of these DNA repair factors during OIS. This study reveals a new functional relationship between the oncogene Ras, the vitamin D/VDR axis, and the expression of DNA repair factors, in the context of OIS. The observed deficiencies in DNA repair factors in senescent cells could contribute to the genomic instability that allows senescence bypass and tumorigenesis.

Model of functional relationship between vitamin D/VDR axis and DNA repair factors during Ras-induced senescence.




Vitamin D receptor signaling improves Hutchinson-Gilford Progeria Syndrome cellular phenotypes.


Ray Kreienkamp, Monica Croke, Martin A. Neumann, Gonzalo Bedia-Diaz, Simona Graziano, Adriana Dusso, Dale Dorsett, Carsten Carlberg, and Susana Gonzalo.


Oncotarget. In press, 2016.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a devastating incurable premature aging disease caused by accumulation of progerin, a toxic lamin A mutant protein. HGPS patient-derived cells exhibit nuclear morphological abnormalities, altered signaling pathways, genomic instability, and premature senescence.

This study uncovers new molecular mechanisms contributing to cellular decline in progeria. We demonstrate that HGPS cells reduce expression of vitamin D receptor (VDR) and DNA repair factors BRCA1 and 53BP1 with progerin accumulation, and that reconstituting VDR signaling via vitamin D (1,25D) treatment improves HGPS phenotypes, including nuclear morphological abnormalities, DNA repair defects, and premature senescence. Importantly, we discovered that the vitamin D/VDR axis regulates LMNA gene expression, as well as expression of DNA repair factors. Vitamin D dramatically reduces progerin production in HGPS cells, while stabilizing BRCA1 and 53BP1, two key factors for genome integrity. Vitamin D/VDR axis emerges as a new target for treatment of HGPS and potentially other lamin-related diseases exhibiting VDR deficiency and genomic instability. Because progerin expression increases with age, maintaining vitamin D/VDR signaling could keep the levels of progerin in check during physiological aging.