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bioRxiv · 10.64898/2026.11.05.764592

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

Lu, W.·Wang, X.·Li, Y.·Chen, P.·Zhu, Y.·Ye, S.
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Abstract

How embryonic stem cells (ESCs) maintain genomic integrity while sustaining self-renewal remains poorly understood. We find that transcription factor CP2-like 1 (Tfcp2l1) recruits Thrap3 in mouse ESCs, where this complex maintains RNA polymerase II activity and promotes transcription of Tfcp2l1 target genes. In addition, Thrap3 supports mESC self-renewal. Interestingly, knockdown of either Tfcp2l1 or Thrap3 induces highly overlapping alternative-splicing changes, including reduced inclusion of exon-5 in Jmjd1c. Further studies reveal that skipping of Jmjd1c exon-5 weakens the association between Jmjd1c and Mdc1, accompanied by elevated Mdc1-associated dimethylation, leading to reduced Mdc1 and Rnf8 interaction and diminished K63-linked ubiquitin signalling. These alterations impair chromatin recruitment of the Rap80 and Brca1 repair complex and increase Rad51 foci formation, indicative of a shift in DNA repair pathway preference. Accordingly, loss of Tfcp2l1 or Thrap3 results in accumulated DNA damage, hypersensitivity to genotoxic stress, compromised ESC self-renewal and enhanced apoptosis. Similar phenotypes can be recapitulated in human ESCs. Together, our findings provide new insights into how ESCs coordinate genome maintenance with self-renewal.

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Lu, W., Wang, X., Li, Y., Chen, P., Zhu, Y., Ye, S.. 2026-11-09. Tfcp2l1 recruits Thrap3 to sustain ESC self-renewal via Jmjd1c exon-5 splicing and DNA repair choice. https://doi.org/10.64898/2026.11.05.764592

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