NEAT1 modulates the TIRR/53BP1 complex to maintain genome integrity
Tudor Interacting Repair Regulator (TIRR) is an RNA-binding protein (RBP) that interacts directly with 53BP1, restricting its access to DNA double-strand breaks (DSBs) and its association with p53. We utilized iCLIP to identify RNAs that directly bind to TIRR within cells, identifying the long non-coding RNA NEAT1 as the primary RNA partner. The high affinity of TIRR for NEAT1 is due to prevalent G-rich motifs in the short isoform (NEAT1_1) region of NEAT1. This interaction destabilizes the TIRR/53BP1 complex, promoting 53BP1's function. NEAT1_1 is enriched during the G1 phase of the cell cycle, thereby ensuring that TIRR-dependent inhibition of 53BP1's function is cell cycle-dependent. TDP-43, an RBP that is implicated in neurodegenerative diseases, modulates the TIRR/53BP1 complex by promoting the production of the NEAT1 short isoform, NEAT1_1. Together, we infer that NEAT1_1, and factors regulating NEAT1_1, may impact 53BP1-dependent DNA repair processes, with implications for a spectrum of diseases.
Authors
- Dipanjan Chowdhury (ORCID: https://orcid.org/0000-0001-5645-3752)
- Maria Victoria Botuyan (ORCID: https://orcid.org/0000-0002-6466-7432)
- Patrick Toolan-Kerr (ORCID: https://orcid.org/0000-0002-7970-649X)
- Anna R. Poetsch (ORCID: https://orcid.org/0000-0003-3056-4360)
- Aleem Syed (ORCID: https://orcid.org/0000-0001-7942-3900)
- Gaofeng Cui (ORCID: https://orcid.org/0000-0001-5267-9033)
- Georges Mer (ORCID: https://orcid.org/0000-0002-1900-1578)
- Shrabasti Roychoudhury
- Susan Kilgas (ORCID: https://orcid.org/0000-0003-1012-9230)
- Pascal Drané (ORCID: https://orcid.org/0009-0002-9413-4159)
- Michelle Swift (ORCID: https://orcid.org/0000-0003-3645-1308)
- Mikayla Quigley (ORCID: https://orcid.org/0000-0002-5143-9879)
- Jernej Ule (ORCID: https://orcid.org/0000-0002-2452-4277)
- Aniruddha Sarkar (ORCID: https://orcid.org/0000-0002-9393-1335)
- Sarah E. Wilkins (ORCID: https://orcid.org/0000-0003-1347-3328)
Institutions
- Boston Children's Hospital (US)
- Harvard University (US)
- The Francis Crick Institute (GB)
- Yale University (US)
- Dana-Farber Cancer Institute (US)
- Mayo Clinic in Arizona (US)
- UK Dementia Research Institute (GB)
- Dana-Farber/Harvard Cancer Center (US)
- Center for Systems Biology Dresden (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-30
- DOI
- https://doi.org/10.1038/s41467-024-52862-w
- Citations
- 12
- Primary Topic
- CRISPR and Genetic Engineering
- Type
- article
- Field-Weighted Citation Impact
- 2.81
Funders
- U.S. Department of Defense
- Wellcome Trust
- Francis Crick Institute
- Gray Foundation
- Cancer Research UK
- European Commission
- Deutsche Krebshilfe
- National Institutes of Health
- University of Illinois at Urbana-Champaign
- Medical Research Council
- National Cancer Institute
- National Institute of General Medical Sciences
- Office of Research Infrastructure Programs, National Institutes of Health