Abstract 5457: Structural and functional assessment of mutations identified in different breast cancer genes

Abstract

Abstract Atomic protein structure helps in understanding the functions associated with protein molecule. Therefore, it is very important to correlate the structural information from the biological functions of proteins for translational research. So far, BRCA1 and BRCA2 (Breast Cancer Susceptibility genes 1 and 2) genes have been extensively studied genes for hereditary breast and ovarian cancers. BRCA1 comprises 1863 amino acids and is involved in the tumour suppressor function. It also plays an important role in cell cycle checkpoint control and DNA damage repair process. Germ-line mutations discovered in BRCA1 and BRCA2 genes are distributed all over gene coding regions. BRCA1 encompasses different functional domains like RING-domain at N- terminus, DNA binding domain at the centre and tandem repeats of BRCT at C-terminus. RING-domain of BRCA1 interacts with BARD1, BAP1 whereas C-terminal region of BRCA1 interacts with BACH1, CtIP, Abraxas and controls the cell -cycle checkpoint through the protein-protein interactions. Germ-line mutations identified from the larger cohort of patients is available in different databases. However, unreported mutations are also regularly detected in clinical settings. We have evaluated the folding pattern of mutations discovered in different domains of BRCA1 and BRCA2 using in-silico, in-vitro and biophysical approaches. Furthermore, studies of protein-protein interactions (PPIs) with the binding partners of BRCA1 such as RAP80, MERIT40, and ABRAXAS have been explored using isothermal titration calorimetry. The slight differences between wild-type and mutant proteins of BRCA1 and BRCA2 have been observed. The data obtained from Circular- Dichroism, protein-protein interactions and structural analysis confirm that an alterations in protein folding pattern although not able to serve as a sole tool for mutation pathogenicity assessment, could provide valuable information to aid the classification of uncertain, potentially disease-causing, variants in the human cancer-relevant genes. Grant number: DST (Grant DST/INT/RUS/RSF/11), Russian foundation for Basic research (grant number 19-515-25001) Citation Format: Neha Mishra, Mudassar Ali Khan, Ekaterina S. Kuligina, Syed Hasan, Ashok K. Varma. Structural and functional assessment of mutations identified in different breast cancer genes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5457.