American Association for Cancer Research
15417786mcr200396-sup-242420_2_supp_6457275_q969rd.pdf (937.18 kB)

Supplementary Figure S2 from Platinum-Induced Ubiquitination of Phosphorylated H2AX by RING1A Is Mediated by Replication Protein A in Ovarian Cancer

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journal contribution
posted on 2023-04-03, 19:46 authored by Shruthi Sriramkumar, Timothy D. Matthews, Ahmed H. Ghobashi, Samuel A. Miller, Pamela S. VanderVere-Carozza, Katherine S. Pawelczak, Kenneth P. Nephew, John J. Turchi, Heather M. O'Hagan

RING1A monoubiquitinates phosphoH2AX at lysine 119 in response to cisplatin treatment


Ovarian Cancer Research Alliance

Doane and Eunice Dahl Wright

Van Andel Institute



Platinum resistance is a common occurrence in high-grade serous ovarian cancer and a major cause of ovarian cancer deaths. Platinum agents form DNA cross-links, which activate nucleotide excision repair (NER), Fanconi anemia, and homologous recombination repair (HRR) pathways. Chromatin modifications occur in the vicinity of DNA damage and play an integral role in the DNA damage response (DDR). Chromatin modifiers, including polycomb repressive complex 1 (PRC1) members, and chromatin structure are frequently dysregulated in ovarian cancer and can potentially contribute to platinum resistance. However, the role of chromatin modifiers in the repair of platinum DNA damage in ovarian cancer is not well understood. We demonstrate that the PRC1 complex member RING1A mediates monoubiquitination of lysine 119 of phosphorylated H2AX (γH2AXub1) at sites of platinum DNA damage in ovarian cancer cells. After platinum treatment, our results reveal that NER and HRR both contribute to RING1A localization and γH2AX monoubiquitination. Importantly, replication protein A, involved in both NER and HRR, mediates RING1A localization to sites of damage. Furthermore, RING1A deficiency impairs the activation of the G2–M DNA damage checkpoint, reduces the ability of ovarian cancer cells to repair platinum DNA damage, and increases sensitivity to platinum. Elucidating the role of RING1A in the DDR to platinum agents will allow for the identification of therapeutic targets to improve the response of ovarian cancer to standard chemotherapy regimens.