Senataxin Ortholog Sen1 Limits DNA:RNA Hybrid Accumulation at DNA Double-Strand Breaks to Control End Resection and Repair Fidelity

An important but still enigmatic function of DNA:RNA hybrids is their role in DNA double-strand break (DSB) repair. Here, we show that Sen1, the budding yeast ortholog of the human helicase Senataxin, is recruited at an HO endonuclease-induced DSB and limits the local accumulation of DNA:RNA hybrids...

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Bibliographic Details
Published in:Cell reports (Cambridge) 2020-05, Vol.31 (5), p.107603, Article 107603
Main Authors: Rawal, Chetan C., Zardoni, Luca, Di Terlizzi, Matteo, Galati, Elena, Brambati, Alessandra, Lazzaro, Federico, Liberi, Giordano, Pellicioli, Achille
Format: Article
Language:English
Subjects:
Dna2
DNA:RNA hybrid
DSB repair
DSB resection
Mre11
Sen1/Senataxin
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Summary:An important but still enigmatic function of DNA:RNA hybrids is their role in DNA double-strand break (DSB) repair. Here, we show that Sen1, the budding yeast ortholog of the human helicase Senataxin, is recruited at an HO endonuclease-induced DSB and limits the local accumulation of DNA:RNA hybrids. In the absence of Sen1, hybrid accumulation proximal to the DSB promotes increased binding of the Ku70-80 (KU) complex at the break site, mutagenic non-homologous end joining (NHEJ), micro-homology-mediated end joining (MMEJ), and chromosome translocations. We also show that homology-directed recombination (HDR) by gene conversion is mostly proficient in sen1 mutants after single DSB. However, in the absence of Sen1, DNA:RNA hybrids, Mre11, and Dna2 initiate resection through a non-canonical mechanism. We propose that this resection mechanism through local DNA:RNA hybrids acts as a backup to prime HDR when canonical pathways are altered, but at the expense of genome integrity. [Display omitted] •Sen1 is recruited to DSBs in a Mre11-dependent manner•DNA:RNA hybrids and repair factor KU persist at DSBs in the absence of Sen1•DNA:RNA hybrids drive Mre11-Dna2-dependent non-canonical DSB resection initiation•Non-canonical DSB resection initiation causes elevated NHEJ and translocations Rawal et al. identify a non-canonical mechanism of DSB processing in yeast cells lacking the Senataxin ortholog Sen1 helicase, which strictly depends on DNA:RNA hybrid formation at the break and is associated with unfaithful DSB repair and genome instability.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2020.107603