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PubMed · 42748571

The role of CHAMP1 in chromatin-mediated DNA damage repair.

Felix Y Zhou·Jinal A Patel·Aindri H Patra·Sirisha Mukkavalli·Alan D D'Andrea
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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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CHAMP1DNA damage responseFanconi AnemiaH3K9me3Replication stress responseSynthetic lethalityJournal Article

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Felix Y Zhou, Jinal A Patel, Aindri H Patra, Sirisha Mukkavalli, Alan D D'Andrea. 2026-09-05. The role of CHAMP1 in chromatin-mediated DNA damage repair.. https://doi.org/10.1016/j.dnarep.2026.103958

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PubMed2026

CHAMP1-Related Neurodevelopmental Disorder: Two Turkish Cases with Novel Truncating Variants and Literature Review.

INTRODUCTION: CHAMP1-related neurodevelopmental disorder (CHAMP1-NDD; neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features; MIM: 616579) is a rare autosomal-dominant condition caused by de novo truncating variants leading to haploinsufficiency. The phenotype is characterized by global developmental delay, intellectual disability, severe speech impairment, hypotonia, distinctive craniofacial features, and variable multisystem involvement. CASE PRESENTATION: We describe two unrelated girls harboring novel de novo truncating CHAMP1 variants. Both presented with global developmental delay, profound speech impairment, hypotonia, postnatal growth impairment, and characteristic craniofacial features. Neuroimaging demonstrated normal findings in 1 patient and a thin corpus callosum in the other. Additional manifestations included high-grade vesicoureteral reflux in one individual and sensory dysregulation, reduced pain sensitivity, early-onset hyperphagia, and recurrent respiratory infections in the other. Perinatal complications were noted in one case; however, the overall phenotype was considered primarily attributable to the underlying genetic diagnosis. Exome sequencing identified heterozygous truncating variants, NM_032436.4:c.2081_2082del; p.Ser694* and NM_032436.4:c.2062dup; p.Glu688Glyfs*8, both confirmed as de novo and classified as likely pathogenic according to American College of Medical Genetics and Genomics (ACMG) criteria. CONCLUSION: These cases expand the mutational spectrum of CHAMP1 and further delineate the phenotypic variability of this disorder, highlighting under-recognized systemic and behavioral features. Recognition of these additional clinical observations may facilitate earlier diagnosis and multidisciplinary management, although further studies in larger cohorts are required to clarify their clinical relevance.

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