# Structure and Mechanism of Non-Homologous End Joining

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $360,229

## Abstract

Summary
Among all different types of DNA damages, double strand breaks (DSBs) are viewed as the most toxic ones
that lead to genome instability. They are created by either endogenous agents such as reactive oxygen
species, or exogenous ionizing radiation and chemicals. Unrepaired DSBs drive apoptosis and senescence,
and incorrect DSB repair can lead to undesired genome rearrangements, such as deletions, translocations,
and fusions. Non-homologous end-joining (NHEJ) pathway, in which the two broken DNA ends are directly
ligated without referring to a homologous template, is the primary DSB repair pathway that remains active
throughout the cell cycle. NHEJ is also responsible for the assembly of gene segments in V(D)J recombination,
where various immunoglobulin genes are generated by exon recombination in immune cells. NHEJ is initialized
by Ku heterodimer (Ku70/80) recognizing DSB ends. Upon recognizing a dsDNA broken end, Ku70/80 recruits
the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and assembles into the so-called DNA-PK
holoenzyme. Other evolutionarily conserved NHEJ factors, including components of the ligase complex (DNA
ligase IV, XRCC4 and XLF) are then recruited to the end reparation site. Successful DSB repair through NHEJ
relies on the efficient bridging of two broken DNA ends, and this proposal aims to investigate the mechanism of
NHEJ by directly visualizing the key steps of repair using single-particle cryo-EM. A more refined picture of the
system specifically recognizing and correcting DSBs will provide an unprecedented, comprehensive view of
these essential molecular machines during operation, and could lead to the development of novel treatments
for various types of human cancer.

## Key facts

- **NIH application ID:** 9867097
- **Project number:** 1R01GM135651-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Yuan He
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $360,229
- **Award type:** 1
- **Project period:** 2020-02-11 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867097

## Citation

> US National Institutes of Health, RePORTER application 9867097, Structure and Mechanism of Non-Homologous End Joining (1R01GM135651-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9867097. Licensed CC0.

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