TRIP13 Participates in Immediate-Early Sensing of DNA Strand Breaks and ATM Signaling Amplification through MRE11

Abstract

Thyroid hormone receptor-interacting protein 13 (TRIP13) participates in various regulatory steps related to the cell cycle, such as the mitotic spindle assembly checkpoint and meiotic recombination, possibly by interacting with members of the HORMA domain protein family. Recently, it was reported that TRIP13 could regulate the choice of the DNA repair pathway, i.e., homologous recombination (HR) or nonhomologous end-joining (NHEJ). However, TRIP13 is recruited to DNA damage sites within a few seconds after damage and may therefore have another function in DNA repair other than regulation of the pathway choice. Furthermore, the depletion of TRIP13 inhibited both HR and NHEJ, suggesting that TRIP13 plays other roles besides regulation of choice between HR and NHEJ. To explore the unidentified functions of TRIP13 in the DNA damage response, we investigated its genome-wide interaction partners in the context of DNA damage using quantitative proteomics with proximity labeling. We identified MRE11 as a novel interacting partner of TRIP13. TRIP13 controlled the recruitment of MDC1 to DNA damage sites by regulating the interaction between MDC1 and the MRN complex. Consistently, TRIP13 was involved in ATM signaling amplification. Our study provides new insight into the function of TRIP13 in immediate-early DNA damage sensing and ATM signaling activation.

Genome-wide methylation profiling of Peripheral T-cell lymphomas identifies TRIP13 as a critical driver of tumor proliferation and survival

“…5A). To determine if any of these genes may play a role in PTCL maintenance, we utilized data from CRISPR knockout screens in the DepMap database (Broad Institute, (39,40)) and investigated whether any of the genes affected the growth of hematologic cell lines. This search revealed that knockouts of most genes did not signi cantly impact the proliferation of hematological cell lines, as indicated by the gene effect scores ranging from − 0.75 to + 0.75 (Figs.…”

“…The AAA ATPase TRIP13 (thyroid hormone receptor interactor 13) is known to participate in various regulatory steps related to the cell cycle, such as the mitotic spindle assembly checkpoint and meiotic recombination, as well as the DNA repair by immediate-early DNA damage sensing and ATM signaling activation 39 . To determine if TRIP13 is required for the proliferation of PTCL, we transduced a PTCL-NOS cell line, T8ML-1, with lentiviruses expressing shRNAs either targeting scrambled or TRIP13 and coexpressing mCherry.…”

Targeting TRIP13 for overcoming anticancer drug resistance (Review)

“…Thyroid hormone receptor interactor 13 (TRIP13) is a member of the AAA+ ATPase family able to generate mechanical stresses through ATP hydrolase activities ( 1 ). TRIP13 was initially identified as a protein that interacts with the E1 protein of the human papillomavirus ( 2 ).…”