Mutations in Mre11 Induce Genomic Instability

Exogenous agents such as ionizing radiation that challenge the DNA and produces various DNA lesions lead to genome instability. These lesions at the DNA level led to changes in genetic information, leading to mutagenesis, which can propagate in subsequent rounds of replication, eventually resulting in the disruption of normal cell function, and uncontrolled cell growth thus forming tumors. DNA double strand breaks (DSBs) are the most lethal type of DNA damage that cells combat. One of the pathways to repair DSBs is homology-dependent repair (HDR). The 3′-to-5′ exonuclease activity of Mre11 generate protruding 3′ ssDNA at DSBs. Further, Rad51, a factor that performs homology search and strand invasion, then binds the ssDNA. Mre11 is responsible for the initial short-range resection which is followed by the long resection by Exo1 before strand invasion in HDR. The purpose of this study is to test the hypothesis that MRE11 gene variants contribute to genomic instability by aberrant DNA repair. This project seeks to understand the potential role of disease-associated variants of Mre11 in defective resection function thus inducing genomic instability.