CAREER: Defining the Initiation of Recombination at DNA Double Strand Breaks

DNA, which codes genetic information, can be damaged by both environmental insults and normal biological processes. Cells have numerous mechanisms to repair damaged DNA, some of which maintain the encoded information and some that alter it. This study leverages novel methods to understand how cells choose different mechanisms to repair one type of DNA damage, the double strand break.

The work will address key questions, including how cells commit to recombination, a class of DNA repair mechanisms that copy damaged DNA using a template molecule and maintain encoded information. Results from this study will have broad implications for fields like gene editing, cancer treatment, and personalized medicine. Additionally, this project will provide training and research experiences to junior transfer college students with the goal of improving academic success and retention in STEM fields.

Together these activities promise to improve both our understanding of DNA repair and the accessibility of science education.

The research will define how human cells control the initiation and early steps of recombination at DNA double strand breaks (DSBs). This project leverages the recent discovery that covalent modification of DNA with interstrand crosslinks enhances recombination frequency. Crosslink-stimulated recombination will be used to boost recombination frequencies at DSBs, thereby enabling the analysis of key recombination activation mechanisms through advanced microscopy, molecular biology, and biochemical techniques.

Objective 1 of this project will define which step of recombination is altered in crosslink-stimulated recombination. Objective 2 will explore how the DNA repair regulatory kinase ATR is activated during DSB repair. Objective 3 will develop a new and comprehensive understanding of DSB repair factors involved in recombination.

All objectives will integrate a cohort of pre-biology transfer students into this project through mentorship and authentic research experiences, thereby supporting their retention and success in STEM fields.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.