Martha Huitron
Research Mentor: Joann Sekiguchi
Mentor Department: Internal Medicine and Department of Human Genetics, Medicine
Author(s): Martha Huitron, Andrea Hartlerode, McKenna DeFoer, JoAnn Sekiguchi
Session: Session 3 (11:00 AM – 11:50 AM)
Presentation Type: Poster 38
Abstract
The MRE11-RAD50-NBS1 (MRN) complex is a group of proteins that plays a key role in protecting cells from unrepaired DNA damage by detecting and repairing breaks in both strands of the DNA molecule, known as double-strand breaks (DSBs). In addition to activating DNA damage signaling through the ATM kinase, the MRN complex directly processes DNA ends and participates in all major double-strand break repair pathways to maintain genome stability. Mutations in the MRE11 gene can lead to a rare, inherited neurodegenerative condition called ataxia-telangiectasia–like disorder (ATLD), which primarily affects children and is associated with increased sensitivity to DNA damage. ATLD patient alleles are located within key MRE11 functional domains and can lead to markedly reduced levels of the entire MRN complex; however, it is unknown whether ATLD phenotypes arise from loss of distinct MRN functions, low MRE11 protein levels, or both. In this study, we examined how specific pathogenic MRE11 variants and/or MRN expression levels contribute to chromosomal instability using mutant mouse models and cultured cells. Multiple mouse models were engineered to express either wild-type MRE11 or MRE11 disease alleles at endogenous or low levels. In parallel, we analyzed cells carrying a hypomorphic disease allele of the DNA repair factor Artemis (P70), as well as double mutants combining Artemis P70 with the MRE11-ATLD1 allele, to assess genetic interactions between DNA repair pathways. Chromosomal metaphase spreads were prepared, imaged, and analyzed to identify structural abnormalities such as chromosome and chromatid breaks, Robertsonian translocations, and fusions. By comparing these measurements across genotypes, this study provides insight into how specific defects in MRN complex function, either alone or in combination with impaired Artemis activity, contribute to genomic instability in ATLD.
