Crystal structure of the human MUS81-EME2 complex

Hua, Zhengkang; Fang, Qianqian; Zhang, Danping; Luo, Zhipu; Yuan, Cai; Lin, Zhonghui

doi:10.1016/j.str.2022.02.015

Cited by 7 publications

(2 citation statements)

References 42 publications

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“…Besides removing HR intermediates arising from recombinational DNA transactions, both SSEs process persistent replication intermediates to promote the completion of genome replication and sister chromatid disentanglement ( Falquet and Rass, 2019 ). MUS81 complexes can cleave replication forks, structures resembling intact HJs such as four-way reversed forks, and D-loops to initiate and regulate BIR as a mechanism to repair dysfunctional forks ( Hanada et al, 2007 ; Hua et al, 2022 ; Kikuchi et al, 2013 ; Mayle et al, 2015 ; Pepe and West, 2014a ; Pepe and West, 2014b ). MUS81 is also essential for the ‘expression’ of common fragile sites (CFSs)—sites that are prone to under-replication during stressed conditions—by cleaving stalled replication forks to enable POLD3-mediated mitotic DNA synthesis (MiDAS) ( Debatisse et al, 2012 ; Minocherhomji et al, 2015 ; Naim et al, 2013 ; Ying et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

The structure-selective endonucleases GEN1 and MUS81 mediate complementary functions in safeguarding the genome of proliferating B lymphocytes

Fernandez

Feeney

Smolkin

et al. 2022

eLife

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During the development of humoral immunity, activated B lymphocytes undergo vigorous proliferative, transcriptional, metabolic, and DNA remodeling activities; hence, their genomes are constantly exposed to an onslaught of genotoxic agents and processes. Branched DNA intermediates generated during replication and recombinational repair must be eliminated to preserve the integrity of these DNA transactions for the faithful duplication and propagation of genomic material. To investigate the role of two structure-selective endonucleases, GEN1 and MUS81, in B cell biology, we established B-cell conditional knockout mouse models and found that targeted deletion of GEN1 and MUS81 in early B-cell precursors abrogates the development and maturation of B-lineage cells while selective loss of the enzymes in mature B cells inhibits the generation of robust germinal centers. Upon activation, these double-null mature B lymphocytes fail to proliferate and survive while exhibiting transcriptional signatures of p53 signaling, apoptosis, and type I interferon response. Metaphase spreads of these endonuclease-deficient cells showed severe and diverse chromosomal abnormalities, including a preponderance of chromosome breaks, consistent with a defect in resolving DNA recombination intermediates. These observations underscore the pivotal roles of GEN1 and MUS81 in safeguarding the genome to ensure the proper development and maintenance of B lymphocytes.

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Section: Introductionmentioning

confidence: 99%

The structure-selective endonucleases GEN1 and MUS81 mediate complementary functions in safeguarding the genome of proliferating B lymphocytes

Fernandez

Feeney

Smolkin

et al. 2022

eLife

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show abstract

“…Successful HJ resolution requires two stepwise incisions across the junction center, which is catalyzed by a group of structure-selective DNA endonucleases, namely HJ resolvases 2 . Based on the substrate specificity, HJ resolvases can be divided into two major categories 3 : (1) the canonical HJ resolvases, which includes RuvC [4][5][6] , Hjc 4 , Cce1 / Ydc2 5-8 , GEN1 [9][10][11][12][13][14] , and MOC1 15,16 ; and (2) the noncanonical HJ resolvases, such as SLX1-SLX4 [17][18][19][20] and MUS81-EME1/2 [21][22][23] . Canonical HJ resolvases introduce two symmetrical nicks across the junction center by functioning as homodimers, and exhibit strong structure-and sequence-specificities in HJ cleavage.…”

mentioning

confidence: 99%

MOC1 cleaves Holliday junctions through a cooperative nick and counter-nick mechanism mediated by metal ions

Zhang,

Xu,

Luo

et al. 2024

Nat Commun

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Holliday junction resolution is a crucial process in homologous recombination and DNA double-strand break repair. Complete Holliday junction resolution requires two stepwise incisions across the center of the junction, but the precise mechanism of metal ion-catalyzed Holliday junction cleavage remains elusive. Here, we perform a metal ion-triggered catalysis in crystals to investigate the mechanism of Holliday junction cleavage by MOC1. We capture the structures of MOC1 in complex with a nicked Holliday junction at various catalytic states, including the ground state, the one-metal ion binding state, and the two-metal ion binding state. Moreover, we also identify a third metal ion that may aid in the nucleophilic attack on the scissile phosphate. Further structural and biochemical analyses reveal a metal ion-mediated allosteric regulation between the two active sites, contributing to the enhancement of the second strand cleavage following the first strand cleavage, as well as the precise symmetric cleavage across the Holliday junction. Our work provides insights into the mechanism of metal ion-catalyzed Holliday junction resolution by MOC1, with implications for understanding how cells preserve genome integrity during the Holliday junction resolution phase.

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Identification of small-molecule inhibitors of human MUS81-EME1/2 by FRET-based high-throughput screening

Zhang

Chen

et al. 2023

Bioorganic & Medicinal Chemistry

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Crystal structure of the human MUS81-EME2 complex

Cited by 7 publications

References 42 publications

The structure-selective endonucleases GEN1 and MUS81 mediate complementary functions in safeguarding the genome of proliferating B lymphocytes

The structure-selective endonucleases GEN1 and MUS81 mediate complementary functions in safeguarding the genome of proliferating B lymphocytes

MOC1 cleaves Holliday junctions through a cooperative nick and counter-nick mechanism mediated by metal ions

Identification of small-molecule inhibitors of human MUS81-EME1/2 by FRET-based high-throughput screening

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