Abstract
DNA double strand breaks (DSBs) can be repaired by either recombination-based or direct ligation-based mechanisms. Pathway choice is made at the level of DNA end resection, a nucleolytic processing step, which primes DSBs for repair by recombination. Resection is thus under cell cycle control, but additionally regulated by chromatin and nucleosome remodellers. Here, we show that both layers of control converge in the regulation of resection by the evolutionarily conserved Fun30/SMARCAD1 remodeller. Budding yeast Fun30 and human SMARCAD1 are cell cycle-regulated by interaction with the DSB-localized scaffold protein Dpb11/TOPBP1, respectively. In yeast, this protein assembly additionally comprises the 9-1-1 damage sensor, is involved in localizing Fun30 to damaged chromatin, and thus is required for efficient long-range resection of DSBs. Notably, artificial targeting of Fun30 to DSBs is sufficient to bypass the cell cycle regulation of long-range resection, indicating that chromatin remodelling during resection is underlying DSB repair pathway choice.
Highlights
DNA end resection – the nucleolytic digestion of the 5’ strands of a double strand breaks (DSBs) – is essential for the initiation of homologous recombination (HR) or related recombination-based mechanisms
Our study reveals that the function of Fun30/SMARCAD1 at DSBs is cell cycle-regulated via interaction with Dpb11/TOPBP1
This interaction seems to facilitate localization of Fun30 to damaged chromatin in a manner that depends on the 9-1-1 complex
Summary
DNA end resection – the nucleolytic digestion of the 5’ strands of a DSB – is essential for the initiation of homologous recombination (HR) or related recombination-based mechanisms (reviewed in [Cejka, 2015; Symington, 2014; Symington and Gautier, 2011]). Resection interferes with ligation-based repair (non-homologous end-joining, NHEJ) and is the critical step for repair pathway choice. DSB repair pathway choice and DNA end resection are highly regulated during the cell cycle: in G1 phase, little resection occurs and NHEJ is favoured. In S, G2 and M phase, resection is up-regulated and HR becomes more prevalent (Cejka, 2015; Ira et al, 2004; Symington, 2014; Symington and Gautier, 2011). A bypass of this control is not sufficient to allow efficient end resection to occur in G1, suggesting that other factors may be involved in the cell cycle control of DNA end resection
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