Medical University of South Carolina
About Us
The Jimenez Sainz Lab is a research laboratory at the Medical University of South Carolina, Charleston. Our focus is on the study of DNA repair proteins and the alterations of their variants. Our lab is a part of the Biochemistry and Molecular Biology Department and it is located in the Hollings Cancer Center Building. With state-of-the-art equipment and a team of dedicated researchers, we aim to advance our knowledge of DNA repair mechanisms and their role in cancer development.
Our lab is home to a team of experts in the field of DNA repair and cancer research. We are passionate about making breakthroughs in our understanding of DNA repair mechanisms and the role they play in cancer development. With a focus on translational research, our lab is committed to finding innovative solutions to the challenges posed by cancer. We work closely with other research institutions and industry partners to ensure that our findings have a real-world impact. If you would like to learn more about our work, please don't hesitate to get in touch.
DNA is the repository of genetic information for each of our living cells; its integrity and stability are essential to life. Our DNA repair genes maintain intact the DNA in the nucleus of our cells and mutations in these genes can predispose patients to genetic diseases such as cancer. My research group focuses on uncovering the molecular mechanisms, functions, and clinical applications of DNA repair protein mislocalization in cancer biology. Pathogenic mutations in the DNA repair genes BRCA1/2 (BReast CAncer susceptibility gene 1 and 2) and PALB2 (PArtner and Localizer of BRCA2) increase the risk of hereditary breast and ovarian cancer by 60-80%, and contribute to pancreatic, melanoma and prostate cancer risk. Most pathogenic mutations are frameshift and nonsense mutations which disrupt essential domains of BRCA1/2 and PALB2 and/or lead to cytosolic mislocalization. Only 25% of the total genetic variants identified by genetic testing in germline and somatic DNA are pathogenic (of more than 35,000 variants total) whereas 60% are Variants of Uncertain Significance (VUS) with unknown, but possible, connection to disease. Almost all VUS are missense mutations (90%) so there is a need to define how these mutations affect the biochemistry, localization, and nuclear functions of BRCA1/2 and PALB2 (Figure 1).
BRCA1/2 and PALB2, as part of the DNA repair pathway, are key regulators in homology-directed repair (HDR) and fork protection mechanism, which ensures genome instability. For full activity, BRCA1/2 and PALB2 must be transported into the nucleus to repair DNA double-strand breaks (DSBs) and promote RAD51 filament formation and stability. Our previous studies have identified missense mutations that altered BRCA2 cellular localization and provide sensitivity to platinum drugs and PARP inhibitors however is unclear the nuclear/cytosolic molecular regulation of these proteins. Our laboratory addresses the nuclear transport of BRCA1/2 and PALB2, how cancer-driver mutations lead to cytosolic mislocalization and how tumor cells can be sensitized by modulating BRCA1/2 and PALB2 cellular localization (Figure 2).
The principal areas of research are:
1. Define the molecular mechanism(s) regulating nuclear/cytoplasmic shuttling of BRCA1/2 and PALB2 pathogenic missense variants.
2. Determine the impact of BRCA1/2 and PALB2 cellular localization on HDR, fork protection and cytosolic processes.
3. Exploit BRCA1/2 and PALB2 localization as a cancer diagnostic tool and as a therapy.
Dr. Jimenez Sainz' laboratory findings are making a significant impact in our understanding of BRCA1/2 and PALB2 and their nuclear localization as a fundamental biological question. These principal areas of research reveal the alterations in BRCA1/2 and PALB2 variants to predict cancer risk and exploit the cytosolic retention of BRCA1/2 and PALB2 as a cancer therapy.
Figure 1: Pie charts representing the percentages of BRCA2 germline and somatic variants grouped into clinical significance (left) or molecular consequences (right) as reported in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/?term=BRCA2%5Bgene%5D, accessed on 10 April 2021).
Figure 2: Scheme of the scenario to investigate and the questions to address. HDR: Homology-directed repair. Darker color indicates BRCA1/2 and/or PALB2 localization.
