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RHNO1: at the crossroads of DNA replication stress, DNA repair, and cancer

Oncogene volume 43, pages 2613–2620 (2024)Cite this article

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Abstract

The DNA replication stress (DRS) response is a crucial homeostatic mechanism for maintaining genome integrity in the face of intrinsic and extrinsic barriers to DNA replication. Importantly, DRS is often significantly increased in tumor cells, making tumors dependent on the cellular DRS response for growth and survival. Rad9-Hus1-Rad1 Interacting Nuclear Orphan 1 (RHNO1), a protein involved in the DRS response, has recently emerged as a potential therapeutic target in cancer. RHNO1 interacts with the 9-1-1 checkpoint clamp and TopBP1 to activate the ATR/Chk1 signaling pathway, the crucial mediator of the DRS response. Moreover, RHNO1 was also recently identified as a key facilitator of theta-mediated end joining (TMEJ), a DNA repair mechanism implicated in cancer progression and chemoresistance. In this literature review, we provide an overview of our current understanding of RHNO1, including its structure, function in the DRS response, and role in DNA repair, and discuss its potential as a cancer therapeutic target. Therapeutic targeting of RHNO1 holds promise for tumors with elevated DRS as well as tumors with DNA repair deficiencies, including homologous recombination DNA repair deficient (HRD) tumors. Further investigation into RHNO1 function in cancer, and development of approaches to target RHNO1, are expected to yield novel strategies for cancer treatment.

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Fig. 1: Sequence alignment of RHNO1 in vertebrate species, and human RHNO1 structure and functional domains.
Fig. 2: Consensus predictions for human RHNO1 disorder (pink) and binding (blue) regions.
Fig. 3: Cyclebase data of RHNO1 mRNA expression in HeLa cells throughout cell cycle phases.
Fig. 4: Functional interplay of RHNO1 with oncogenic pathways in cancer.
Fig. 5: RHNO1 expression is associated with reduced survival in renal cancer and hepatocellular carcinoma (HCC).

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Acknowledgements

This work was supported by NIH R21CA273399 (ARK, DRR), US Department of Defense HT9425-23-1-0238 (ARK, DRR), the Rivkin Center (ARK), NIH P30CA036727 (ARK, GG), Fred & Pamela Buffett Cancer Center Pilot Award (ARK), and The Betty J. and Charles D. McKinsey Ovarian Cancer Research Fund (ARK).

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Authors and Affiliations

  1. Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE, 68198-6805, USA

    Niphat Jirapongwattana & Adam R. Karpf

  2. Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-6805, USA

    Niphat Jirapongwattana, Gargi Ghosal & Adam R. Karpf

  3. Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854-8021, USA

    Samuel F. Bunting

  4. Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198-6805, USA

    Donald R. Ronning

  5. Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198-6805, USA

    Gargi Ghosal

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NJ and ARK drafted, edited, and prepared the final version of the manuscript. SFB, DRR, and GG edited the manuscript. NJ, ARK, and DRR prepared figures. All authors approved the final version of the manuscript.

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Correspondence to Adam R. Karpf.

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Jirapongwattana, N., Bunting, S.F., Ronning, D.R. et al. RHNO1: at the crossroads of DNA replication stress, DNA repair, and cancer. Oncogene 43, 2613–2620 (2024). https://doi.org/10.1038/s41388-024-03117-x

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