Details

Autor(en) / Beteiligte

• Tsukada, Kaima
• Jones, Samuel E.
• Bannister, Julius
• Durin, Mary-Anne
• Vendrell, Iolanda
• Fawkes, Matthew
• Fischer, Roman
• Kessler, Benedikt M.
• Chapman, J. Ross
• Blackford, Andrew N.

Titel

BLM and BRCA1-BARD1 coordinate complementary mechanisms of joint DNA molecule resolution

Ist Teil von

• Molecular cell, 2024-02, Vol.84 (4), p.640-658.e10

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2024

Quelle

Elsevier ScienceDirect Journals Complete

Beschreibungen/Notizen

• The Bloom syndrome helicase BLM interacts with topoisomerase IIIα (TOP3A), RMI1, and RMI2 to form the BTR complex, which dissolves double Holliday junctions and DNA replication intermediates to promote sister chromatid disjunction before cell division. In its absence, structure-specific nucleases like the SMX complex (comprising SLX1-SLX4, MUS81-EME1, and XPF-ERCC1) can cleave joint DNA molecules instead, but cells deficient in both BTR and SMX are not viable. Here, we identify a negative genetic interaction between BLM loss and deficiency in the BRCA1-BARD1 tumor suppressor complex. We show that this is due to a previously overlooked role for BARD1 in recruiting SLX4 to resolve DNA intermediates left unprocessed by BLM in the preceding interphase. Consequently, cells with defective BLM and BRCA1-BARD1 accumulate catastrophic levels of chromosome breakage and micronucleation, leading to cell death. Thus, we reveal mechanistic insights into SLX4 recruitment to DNA lesions, with potential clinical implications for treating BRCA1-deficient tumors. [Display omitted] •RECQL5 counteracts RAD51 filament formation, but BLM does not•Combined deficiency in BLM and BRCA1-BARD1 (but not BRCA2) is synthetic lethal•BARD1 recruits SLX4 and MUS81 to resolve DNA intermediates left unprocessed by BLM•The phosphorylated BARD1 MUSIC motif interacts with SLX4 in a CDK1-dependent manner Tsukada et al. identify a negative genetic interaction between the BLM helicase and the BRCA1-BARD1 complex. They reveal that this is due to a previously overlooked role for BARD1 in recruiting the SLX4 structure-specific nuclease complex to resolve DNA intermediates and joint molecules left unprocessed by BLM prior to cell division.