PROFESSIONAL HISTORY

Book Review - 2017

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DISTINCT BINDING OF BRCA2 BRC REPEATS TO RAD51 GENERATES DIFFERENTIAL DNA DAMAGE SENSITIVITY

Nucleic Acid Research - 2015

BRCA2 is a multi-faceted protein critical for the proper regulation of homology-directed repair of DNA double-strand breaks. Elucidating the mechanistic features of BRCA2 is crucial for understanding homologous recombination and how patient-derived mutations impact future cancer risk. Eight centrally located BRC repeats in BRCA2 mediate binding and regulation of RAD51 on resected DNA substrates. Herein, we dissect the biochemical and cellular features of the BRC repeats tethered to the DNA binding domain of BRCA2. To understand how the BRC repeats and isolated domains of BRCA2 contribute to RAD51 binding, we analyzed both the biochemical and cellular properties of these proteins. In contrast to the individual BRC repeat units, we find that the BRC5–8 region potentiates RAD51-mediated DNA strand pairing and provides complementation functions exceeding those of BRC repeats 1–4. Furthermore, BRC5–8 can efficiently repair nuclease-induced DNA double-strand breaks and accelerate the assembly of RAD51 repair complexes upon DNA damage. These findings highlight the importance of the BRC5–8 domain in stabilizing the RAD51 filament and promoting homology-directed repair under conditions of cellular DNA damage.

PROMOTION OF BRCA2-DEPENDENT HOMOLOGOUS RECOMBINATION BY DSS1 VIA RPA TARGETING AND DNA MIMICRY

Molecular Cell Volume 59, Issue 2, p176–187 - July 2015

The tumor suppressor BRCA2 is thought to facilitate the handoff of ssDNA from replication protein A (RPA) to the RAD51 recombinase during DNA break and replication fork repair by homologous recombination. However, we find that RPA-RAD51 exchange requires the BRCA2 partner DSS1. Biochemical, structural, and in vivo analyses reveal that DSS1 allows the BRCA2-DSS1 complex to physically and functionally interact with RPA. Mechanistically, DSS1 acts as a DNA mimic to attenuate the affinity of RPA for ssDNA. A mutation in the solvent-exposed acidic domain of DSS1 compromises the efficacy of RPA-RAD51 exchange. Thus, by targeting RPA and mimicking DNA, DSS1 functions with BRCA2 in a two-component homologous recombination mediator complex in genome maintenance and tumor suppression. Our findings may provide a paradigm for understanding the roles of DSS1 in other biological processes.

PINK1 REGULATES HISTONE H3 TRIMETHYLATION AND GENE EXPRESSION BY INTERACTION WITH THE POLYCOMB PROTEIN EED/WAIT1

Proc Natl Acad Sci USA - September 2013

Mutations in PTEN-induced putative kinase 1 (PINK1) gene are associated to early-onset recessive forms of Parkinson disease. PINK1 function is related to mitochondria homeostasis, but the molecular pathways in which PINK1 is involved are largely unknown. Here, we report the identification of the embryonic ectoderm development polycomb histone-methylation modulator (EED/WAIT1) as a PINK1-interacting and -regulated protein. The PINK1:EED/WAIT1 physical interaction was mediated by the PINK1 kinase domain and the EED/WAIT1 40 amino acid ending with tryptophan and aspartate (WD40)-repeat region, and PINK1 phosphorylated EED/WAIT1 in vitro. PINK1 associated with EED/WAIT1 in cells and relocated EED/WAIT1 to the mitochondria. This interaction reduced the trimethylation of lysine 27 from histone H3, which affected polycomb-regulated gene transcription during RA differentiation of SH-SY5Y human neuroblastoma cells. Our findings unveil a pathway by which PINK1 regulates histone methylation and gene expression through the polycomb repressor complex.

PINK1 DISPLAYS TISSUE-SPECIFIC SUBCELLULAR LOCATION AND REGULATES APOPTOSIS AND CELL GROWTH IN BREAST CANCER CELLS.

Hum Pathol. 42(1):75-87 - January 2011

The PINK1 gene is mutated in the germ line of patients with hereditary early-onset Parkinson disease, and PINK1 prosurvival function at neuronal mitochondria has been related with the etiology of this disease. However, the expression and function of PINK1 protein in nonneuronal tissues has not been determined yet. Here, we have analyzed PINK1 protein expression and subcellular distribution in normal and neoplastic human tissues and investigated the function of PINK1 in breast carcinoma cells. PINK1 protein, as stained by a specific anti-PINK1 monoclonal antibody, was widely expressed in human tissues, displaying high expression in epithelial tissues and in the central nervous system and lower expression in tissues of mesenchymal origin. The subcellular distribution of PINK1 was cytoplasmic granular or cytoplasmic diffuse in most tissues. In breast, PINK1 was also associated with the plasma membrane. Human neoplastic tissues ranged from high PINK1 expression in carcinomas to low expression in sarcomas. In neoplastic tissues, PINK1 displayed a diffuse cytoplasmic localization, with an additional membranous localization in breast carcinoma and squamous carcinoma of lung. In the human breast carcinoma Michigan Cancer Foundation-7 cell line, ectopic expression of cytoplasmic or mitochondrial-targeted PINK1 inhibited apoptosis triggered by hydrogen peroxide and suppressed cell growth in soft agar, whereas PINK1 silencing increased hydrogen peroxide-induced apoptosis. Together, our findings indicate that the physiologic functions of PINK1 go beyond its regulatory role of mitochondria-mediated cell survival in neurons.