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Structurally distinct Mre11 domains mediate MRX functions in resection, end-tethering and DNA damage resistance.


ABSTRACT: Sae2 cooperates with the Mre11-Rad50-Xrs2 (MRX) complex to initiate resection of DNA double-strand breaks (DSBs) and to maintain the DSB ends in close proximity to allow their repair. How these diverse MRX-Sae2 functions contribute to DNA damage resistance is not known. Here, we describe mre11 alleles that suppress the hypersensitivity of sae2? cells to genotoxic agents. By assessing the impact of these mutations at the cellular and structural levels, we found that all the mre11 alleles that restore sae2? resistance to both camptothecin and phleomycin affect the Mre11 N-terminus and suppress the resection defect of sae2? cells by lowering MRX and Tel1 association to DSBs. As a consequence, the diminished Tel1 persistence potentiates Sgs1-Dna2 resection activity by decreasing Rad9 association to DSBs. By contrast, the mre11 mutations restoring sae2? resistance only to phleomycin are located in Mre11 C-terminus and bypass Sae2 function in end-tethering but not in DSB resection, possibly by destabilizing the Mre11-Rad50 open conformation. These findings unmask the existence of structurally distinct Mre11 domains that support resistance to genotoxic agents by mediating different processes.

SUBMITTER: Cassani C 

PROVIDER: S-EPMC5888019 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Structurally distinct Mre11 domains mediate MRX functions in resection, end-tethering and DNA damage resistance.

Cassani Corinne C   Gobbini Elisa E   Vertemara Jacopo J   Wang Weibin W   Marsella Antonio A   Sung Patrick P   Tisi Renata R   Zampella Giuseppe G   Longhese Maria Pia MP  

Nucleic acids research 20180401 6


Sae2 cooperates with the Mre11-Rad50-Xrs2 (MRX) complex to initiate resection of DNA double-strand breaks (DSBs) and to maintain the DSB ends in close proximity to allow their repair. How these diverse MRX-Sae2 functions contribute to DNA damage resistance is not known. Here, we describe mre11 alleles that suppress the hypersensitivity of sae2Δ cells to genotoxic agents. By assessing the impact of these mutations at the cellular and structural levels, we found that all the mre11 alleles that res  ...[more]

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