Tfcp2l1 recruits Thrap3 to sustain ESC self-renewal via Jmjd1c exon-5 splicing and DNA repair choice

Tfcp2l1 recruits Thrap3 in mouse embryonic stem cells, sustaining self-renewal by promoting Jmjd1c exon-5 inclusion and DNA repair pathway choice.

• Why it matters: ESCs must preserve genomic integrity while continuing self-renewal, but how transcriptional control links splicing to DNA repair decisions is unclear.
• What they did: In mouse ESCs, Tfcp2l1–Thrap3 maintains RNA polymerase II activity and Tfcp2l1 target transcription; Tfcp2l1 or Thrap3 knockdown causes overlapping splicing changes, including reduced Jmjd1c exon-5 inclusion.
• The result: Exon-5 skipping weakens Jmjd1c–Mdc1 association, alters Mdc1-linked ubiquitin signaling, impairs Rap80/Brca1 chromatin recruitment, increases Rad51 foci, and leads to accumulated DNA damage, genotoxic hypersensitivity, reduced self-renewal, and apoptosis, with similar effects in human ESCs.

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