Johns Hopkins University has received a USD 1.5 million National Cancer Institute R01 renewal to investigate whether alternative splicing of the histone variant macroH2A1 controls cancer cell sensitivity to PARP and topoisomerase 1 (TOP1) inhibitors, potentially identifying a new biomarker of response to established cancer drug classes.
The award, covering fiscal year 2026 through July 2029, supports work led by Philipp Oberdoerffer, in the university's radiation diagnostics and oncology department, examining how the two macroH2A1 splice isoforms regulate repair of single-stranded DNA lesions and influence mutation accumulation and tumor development.
Single-stranded DNA lesions are among the most frequent genomic aberrations in somatic cells and are the primary trigger for poly-(ADP-ribose) polymerase (PARP) activation, which coordinates downstream repair. The Oberdoerffer lab reported in unpublished work that macroH2A1 — an abundant histone H2A variant that exists as two alternative splice isoforms, macroH2A1.1 and macroH2A1.2 — plays an isoform-specific role in this process. MacroH2A1.1 binds poly-(ADP-ribose) derivatives; macroH2A1.2 does not. Preliminary data indicated that macroH2A1.1 levels are inversely correlated with sensitivity to ssDNA lesion-inducing agents across cancer cell lines, suggesting the isoform ratio may function as a determinant of treatment response.
Aberrant macroH2A1 splicing has been observed across multiple cancer types, though its functional consequences have remained poorly characterized. The funded work will use cell-based reporters, genomic approaches, mouse models, and human tumor organoids to test whether macroH2A1 isoform imbalance directly affects mutation accumulation, tumor development, and sensitivity to topoisomerase 1 (TOP1) inhibitors and PARP inhibitors — drug classes that are established in clinical oncology but whose efficacy varies considerably across patients.