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

[UNLABELLED] 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.

[SIGNIFICANCE] 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.