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TRIM44 mediated p62 deubiquitination enhances DNA damage repair by increasing nuclear FLNA and 53BP1 expression

Oncogene volume 40, pages 5116–5130 (2021)Cite this article

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Abstract

Cancer cells show increases in protein degradation pathways, including autophagy, during progression to meet the increased protein degradation demand and support cell survival. On the other hand, reduced autophagy activity during aging is associated with a reduced DNA damage response and increased genomic instability. Therefore, it is a puzzling how DNA repair can be increased in cancer cells that are resistant to chemotherapies or during progression when autophagy activity is intact or increased. We discovered that tripartite motif containing 44 (TRIM44) is a pivotal element regulating the DNA damage response in cancer cells with intact autophagy. TRIM44 deubiquitinates p62, an autophagy substrate, which leads to its oligomerization. This prevents p62 localization to the nucleus upon irradiation. Increased cytoplasmic retention of p62 by TRIM44 prevents the degradation of FLNA and 53BP1, which increases DNA damage repair. Together, our data support TRIM44 a potential therapeutic target for therapy-resistant tumor cells with intact autophagy.

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Fig. 1: TRIM44 promotes ionizing radiation (IR) resistance and protects MM cells from IR-induced cell death.
Fig. 2: TRIM44 enhances DNA damage repair in MM cells.
Fig. 3: TRIM44 promotes NHEJ-mediated DNA repair and genome instability in MM.
Fig. 4: TRIM44 upregulates HR-mediated DNA repair mechanisms and genome instability in MM.
Fig. 5: TRIM44 interacts with p62.
Fig. 6: TRIM44 promotes p62 deubiquitination.
Fig. 7: TRIM44 increases FLNA, RAD51, and 53BP1 expression by inhibiting p62 nuclear translocation after irradiation.
Fig. 8: Knockdown of p62 rescues TRIM44KD-mediated IR sensitivity.

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Acknowledgements

This work is supported by NIH grant (R01CA181319) and CPRIT grant (RP20093) given to NM.

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  1. These authors contributed equally: Lin Lyu, Tsung-Chin Lin.

Authors and Affiliations

  1. Center for Stem Cell and Regenerative Disease, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), the University of Texas-Health Science Center at Houston, Houston, TX, 77030, USA

    Lin Lyu, Tsung-Chin Lin & Nami McCarty

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  1. Lin Lyu
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LL and TCL performed experiments and generated all figures in the manuscript and NM initiated and supervised overall project and write a manuscript.

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Correspondence to Nami McCarty.

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Lyu, L., Lin, TC. & McCarty, N. TRIM44 mediated p62 deubiquitination enhances DNA damage repair by increasing nuclear FLNA and 53BP1 expression. Oncogene 40, 5116–5130 (2021). https://doi.org/10.1038/s41388-021-01890-7

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