Lysosomal Proteome Analysis Involved in Chaperone-Mediated Autophagy and DNA Damage Response

• Grant number: 25/03598-1
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: October 01, 2025
• End date: September 30, 2026
• Field of knowledge: Biological Sciences - Genetics - Mutagenesis
• Principal Investigator: Nicolas Carlos Hoch
• Grantee: Isabeli Yumi Araújo Osawa
• Supervisor: Ivan Dikic
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Goethe University Frankfurt, Germany
• Associated to the scholarship: 22/04325-0 - Role of chaperone-mediated autophagy in DNA repair and its implications in Breast Cancer, BP.DD

Abstract

Autophagy is a catabolic process, highly conserved in eukaryotes, that mediates the degradation of intracellular components and pathogens in lysosomes. Based on the mechanism used for cargo delivery in lysosomes, there are three main types of autophagy: microautophagy (MI), macroautophagy (MA) and chaperone-mediated autophagy (CMA). CMA is selective for degradation of proteins bearing a pentapeptide motif (KFERQ-like). In this process, a cytosolic chaperone (hsc70) individually recognizes and recruits these proteins to the lysosomal membrane. The substrates are then unfolded and translocated to the lysosomal lumen by interacting with the lysosome-associated membrane protein type 2A (LAMP-2A). To maintain cellular homeostasis and protein quality control, CMA is essentially activated under stress conditions, such as starvation, oxidative stress and DNA damage and has regulatory functions by modulating the levels of specific proteins involved in several pathways. In the context of DNA damage response (DDR), proteins play a critical role in detecting, signalling and repairing DNA lesions and therefore, alterations in their regulated degradation or quality control, through processes like CMA, can impact the maintenance of genome stability. Dysfunctions in CMA and DDR, especially DNA repair mechanisms, have been associated with multiple human diseases, including cancer. Among the different types of cancer, breast cancer stands out as the most incident and the leading cause of cancer death among worldwide women. Little is known about the role of CMA in response to DNA damage in breast cancer, thus the main goal of this project is to further explore the DNA repair mechanisms being regulated by CMA, the consequences of defective CMA in DDR and identify novel CMA substrates involved in these pathways.