| First Author | Buco PAV | Year | 2026 |
| Journal | EMBO Rep | Volume | 27 |
| Issue | 7 | Pages | 1759-1788 |
| PubMed ID | 41807760 | Mgi Jnum | J:389052 |
| Mgi Id | MGI:8322303 | Doi | 10.1038/s44319-026-00727-2 |
| Citation | Buco PAV, et al. (2026) Minute amounts of helicase-deficient truncated RECQL4 are sufficient for DNA replication. EMBO Rep 27(7):1759-1788 |
| abstractText | RECQL4, a RecQ family helicase, is essential for DNA replication and genome stability. Mutations in RECQL4 cause severe human disorders yet we do not fully understand its functions, particularly regarding ATP-dependent helicase activity. To understand RECQL4's functions further, we performed a genome-wide forward genetic screen using a murine model harbouring patient-like RECQL4 mutations. We identify KLHDC3, a substrate-binding subunit of the Cullin-RING ligase E3 complex, loss as the most significant rescue allele. KLHDC3 loss restores proliferation and replication in RECQL4-deficient cells by stabilizing trace levels of a truncated RECQL4 fragment containing the N-terminal 480 amino acids, lacking the helicase and C-terminal regions. This RECQL4 fragment forms after Cre-mediated recombination of the Recql4(fl) allele and contains a neo-degron sequence specific for KLHDC3. Although this mechanism does not apply to human mutations, it demonstrates that minimal RECQL4 levels, without any ATPase domain/activity, are sufficient to support DNA replication. This demonstrates that RECQL4 is an essential and non-redundant regulator of DNA replication and cell viability and that this activity does not require its ATP-dependent helicase activity. |
