Interaction and Reciprocal Stabilization of H3.3 and PARP1 Promote DNA Damage Repair and Tumor Progression in Small Cell Lung Cancer.

Abstract

Multiple lines of evidence have highlighted the transcriptional regulatory activity of H3.3 at promoters and telomeres. However, H3.3 may also play transcriptional regulation-independent roles. In this study, we demonstrated that overexpression of H3F3A, the gene encoding H3.3, supported the pathogenesis of small cell lung cancer (SCLC) by protecting PARP1 from degradation. Chromatin-associated H3.3 and PARP1 physically interacted, which required the 645 to 662 amino acid domain of PARP1 and the 20 to 60 amino acid region of H3.3. Notably, the H3.3-PARP1 interaction blocked K48-linked polyubiquitination of PARP1 at K654 and H3.3 at K36, establishing a positive feedback loop that prevented ubiquitin-mediated degradation of both proteins. Functionally, the oncogenic potential of H3.3 and its role in maintaining genomic stability in SCLC could be partially attributed to the H3.3-PARP1 interaction and the subsequent accumulation of PARP1, which preserved DNA damage repair capacity. Overall, these findings uncover a reciprocal stabilization mechanism between PARP1 and H3.3 within the chromatin context that drives SCLC progression, providing valuable insights into the pathophysiologic mechanisms driving this malignancy. H3.3 binds and stabilizes PARP1 to support genomic stability and progression in small cell lung cancer, identifying a nontranscriptional tumor-promoting function of H3.3 and suggesting the potential for targeting the H3.3-PARP1 axis.