TATDN2 resolution of R-loops is required for survival of BRCA1-mutant cancer cells

Aruna S. Jaiswal, Arijit Dutta, Gayathri Srinivasan, Yaxia Yuan, Daohong Zhou, Montaser Shaheen, Doraid T. Sadideen, Austin Kirby, Elizabeth A. Williamson, Yogesh K. Gupta, Shaun K. Olsen, Mingjiang Xu, Eva Loranc, Pramiti Mukhopadhyay, Alexander Pertsemlidis, Alexander J.R. Bishop, Patrick Sung, Jac A. Nickoloff, Robert Hromas

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

BRCA1-deficient cells have increased IRE1 RNase, which degrades multiple microRNAs. Reconstituting expression of one of these, miR-4638-5p, resulted in synthetic lethality in BRCA1-deficient cancer cells. We found that miR-4638-5p represses expression of TATDN2, a poorly characterized member of the TATD nuclease family. We discovered that human TATDN2 has RNA 3′ exonuclease and endonuclease activity on double-stranded hairpin RNA structures. Given the cleavage of hairpin RNA by TATDN2, and that BRCA1-deficient cells have difficulty resolving R-loops, we tested whether TATDN2 could resolve R-loops. Using in vitro biochemical reconstitution assays, we found TATDN2 bound to R-loops and degraded the RNA strand but not DNA of multiple forms of R-loops in vitro in a Mg2+-dependent manner. Mutations in amino acids E593 and E705 predicted by Alphafold-2 to chelate an essential Mg2+ cation completely abrogated this R-loop resolution activity. Depleting TATDN2 increased cellular R-loops, DNA damage and chromosomal instability. Loss of TATDN2 resulted in poor replication fork progression in the presence of increased R-loops. Significantly, we found that TATDN2 is essential for survival of BRCA1-deficient cancer cells, but much less so for cognate BRCA1-repleted cancer cells. Thus, we propose that TATDN2 is a novel target for therapy of BRCA1-deficient cancers.

Original languageEnglish (US)
Pages (from-to)12224-12241
Number of pages18
JournalNucleic acids research
Volume51
Issue number22
DOIs
StatePublished - Dec 11 2023
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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