The Role of CHAMP1 in Chromatin-Mediated DNA Damage Repair
- 1Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 4 Blackfan Street, Boston, MA 02215, USA
- 2Center for DNA Damage and Repair, Dana-Farber Cancer Institute, 4 Blackfan Street, Boston, MA 02215, USA
Abstract
Defects in the replication stress response are major drivers of cancer development and present key targetable vulnerabilities that can be exploited for anti-cancer therapy. Recent studies have identified CHAMP1 as a novel DNA damage repair factor with roles in double-strand break repair and the replication stress response. Mutations in CHAMP1 are associated with the neurodevelopmental disorder CHAMP1 Syndrome. More recently, children with CHAMP1 Syndrome have developed leukemia, suggesting that CHAMP1 mutations are a potential cancer risk factor. CHAMP1 is part of two DNA damage repair complexes: CHAMP1-POGZ-REV7 (Complex I) and CHAMP1-POGZ-HP1α (Complex II). Complex I promotes homologous recombination by removing the Shieldin complex from the ends of double strand breaks and allowing DSB end resection to occur. Complex II enriches heterochromatin content through the recruitment of the methyltransferase SETDB1 to DNA damage sites. Increased heterochromatin at stalled forks is associated with proper fork stability and restart, demonstrating the importance of CHAMP1 in maintaining genomic integrity. Loss of CHAMP1 leads to increased sensitivity to DNA damaging agents and increased dependence on other DNA damage repair pathways, such as the DNA damage checkpoint and the Fanconi Anemia pathway. CHAMP1 is overexpressed in breast and ovarian cancer cells with high levels of replication stress, providing a molecular mechanism for the tolerance of replication stress. These new findings on the relationship of CHAMP1 with well-established DNA damage repair pathways, suggest that targeting CHAMP1 could present a new synthetic lethality opportunity for cancer cells with high levels of replication stress.
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BibTeX
@article{zhou2026role,
title = {{The Role of CHAMP1 in Chromatin-Mediated DNA Damage Repair}},
author = {Felix Y. Zhou and Jinal A. Patel and Aindri H. Patra and Sirisha Mukkavalli and Alan D. D’Andrea},
journal = {DNA repair},
year = {2026},
month = sep,
doi = {10.1016/j.dnarep.2026.103958},
url = {https://doi.org/10.1016/j.dnarep.2026.103958},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - The Role of CHAMP1 in Chromatin-Mediated DNA Damage Repair
AU - Felix Y. Zhou
AU - Jinal A. Patel
AU - Aindri H. Patra
AU - Sirisha Mukkavalli
AU - Alan D. D’Andrea
PY - 2026
DA - 2026/09/05
JO - DNA repair
DO - 10.1016/j.dnarep.2026.103958
UR - https://doi.org/10.1016/j.dnarep.2026.103958
AB - Defects in the replication stress response are major drivers of cancer development and present key targetable vulnerabilities that can be exploited for anti-cancer therapy. Recent studies have identified CHAMP1 as a novel DNA damage repair factor with roles in double-strand break repair and the replication stress response. Mutations in CHAMP1 are associated with the neurodevelopmental disorder CHAMP1 Syndrome. More recently, children with CHAMP1 Syndrome have developed leukemia, suggesting that CHAMP1 mutations are a potential cancer risk factor. CHAMP1 is part of two DNA damage repair complexes: CHAMP1-POGZ-REV7 (Complex I) and CHAMP1-POGZ-HP1α (Complex II). Complex I promotes homologous recombination by removing the Shieldin complex from the ends of double strand breaks and allowing DSB end resection to occur. Complex II enriches heterochromatin content through the recruitment of the methyltransferase SETDB1 to DNA damage sites. Increased heterochromatin at stalled forks is associated with proper fork stability and restart, demonstrating the importance of CHAMP1 in maintaining genomic integrity. Loss of CHAMP1 leads to increased sensitivity to DNA damaging agents and increased dependence on other DNA damage repair pathways, such as the DNA damage checkpoint and the Fanconi Anemia pathway. CHAMP1 is overexpressed in breast and ovarian cancer cells with high levels of replication stress, providing a molecular mechanism for the tolerance of replication stress. These new findings on the relationship of CHAMP1 with well-established DNA damage repair pathways, suggest that targeting CHAMP1 could present a new synthetic lethality opportunity for cancer cells with high levels of replication stress.
SN - 1568-7864
SN - 1568-7856
ER -