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Last update 08 May 2025

MUS81

Last update 08 May 2025

Basic Info

Synonyms

Crossover junction endonuclease MUS81, FLJ44872, MUS81

+ [2]

Introduction

Interacts with EME1 and EME2 to form a DNA structure-specific endonuclease with substrate preference for branched DNA structures with a 5'-end at the branch nick. Typical substrates include 3'-flap structures, replication forks and nicked Holliday junctions. Plays an essential role in mitosis for the processing of stalled or collapsed replication forks (PubMed:28575661).

Drugs associated with MUS81

MUS81 inhibitors(AstraZeneca)

Target

MUS81

Mechanism

MUS81 inhibitors

Active Org.

AstraZeneca PLC

Originator Org.

AstraZeneca PLC

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with MUS81

100 Translational Medicine associated with MUS81

0 Patents (Medical) associated with MUS81

486

Literatures (Medical) associated with MUS81

01 Mar 2025·Trends in Biotechnology

Inducible regulating homologous recombination enables precise genome editing in Pichia pastoris without perturbing cellular fitness

Article

Author: Cai, Peng ; Yao, Lun ; Zhou, Yongjin J ; Li, Yunxia ; Bai, Fan ; Shen, Yiwei

The methylotrophic yeast Pichia pastoris (also known as Komagataella pastoris) is an ideal host for producing proteins and natural products. Enhancing homologous recombination (HR) is helpful for improving the precision of genome editing, but results in stress to cellular fitness and is harmful for industrial applications. To overcome these challenges, we developed a tetracycline repressor protein (TetR)/tetO2 inducible system to dynamically regulate the HR-related gene RAD52 in P. pastoris. This approach significantly improved the positivity rate of single gene deletion to 81%. Furthermore, inducible overexpression of endogenous MUS81-MMS4 resulted in high-efficiency (81%) genome assembly of multiple genes. This inducible system had no adverse effect on cell growth in different media and resulted in greater fatty alcohol production from methanol compared with a strain constitutively overexpressing HR-related genes. We anticipate that this inducible regulation is applicable for enhancing HR for precise genome editing in P. pastoris and other non-conventional microbes without compromising cellular fitness.

27 Feb 2025·Nucleic Acids Research

Genetic dissection of MutL complexes in Arabidopsis meiosis

Article

Author: Pradillo, Mónica ; Santos, Juan L ; Kbiri, Nadia ; Sáez-Zárate, Esperanza ; Dluzewska, Julia ; Ziolkowski, Piotr A ; Pelé, Alexandre ; Dziegielewski, Wojciech ; Mata-Villanueva, Ana ; Fernández-Jiménez, Nadia

AbstractDuring meiosis, homologous chromosomes exchange genetic material through crossing over. The main crossover pathway relies on ZMM proteins, including ZIP4 and HEI10, and is typically resolved by the MLH1/MLH3 heterodimer, MutLγ. Our analysis shows that while MUS81 may partially compensate for MutLγ loss, its role remains uncertain. However, our multiple mutant analysis shows that MUS81 is unlikely to be the sole resolvase of ZMM-protected recombination intermediates when MutLγ is absent. Comparing genome-wide crossover maps of mlh1 mutants with ZMM-deficient mutants and lines with varying HEI10 levels reveals that crossover interference persists in mlh1 but is weakened. The significant crossover reduction in mlh1 also increases aneuploidy in offspring. The loss of MutLγ can be suppressed by eliminating the FANCM helicase. Combined with the lower-than-expected chiasma frequency, this suggests that in MutLγ absence, some ZMM-protected intermediates are ultimately resolved by DNA helicases and/or their complexes with Top3α. Elevated MLH1 or MLH3 expression moderately increases crossover frequency, while their misregulation drastically reduces crossover numbers and plant fertility, highlighting the importance for tight control of MLH1/MLH3 levels. By contrast, PMS1, a component of the MutLα endonuclease, appears uninvolved in crossing over. Together, these findings demonstrate the unique role of MutLγ in ZMM-dependent crossover regulation.

27 Feb 2025·Nucleic Acids Research

MutLγ enforces meiotic crossovers in Arabidopsis thaliana

Article

Author: Durand, Stéphanie ; Solier, Victor ; Fernandes, Joiselle Blanche ; Lian, Qichao ; Mercier, Raphael

AbstractDuring meiosis, each chromosome pair experiences at least one crossover (CO), which directs their balanced segregation in addition to shuffling genetic information. COs tend to be away from each other, a phenomenon known as CO interference. The main biochemical pathway for CO formation, which is conserved in distant eukaryotes, involves the ZMM proteins together with the MLH1–MLH3 complex (MutLγ). Here, we aim to clarify the role of MutLγ in CO formation in Arabidopsis thaliana. We show that AtMutLγ is partially dispensable for ZMM-dependent CO formation. HEI10 large foci—that mark CO sites in wild-type—form at a normal level in mlh1 and mlh3 mutants, but are inefficiently maturated into COs. Mutating the MUS81 nuclease in either mlh1 or mlh3 leads to chromosome fragmentation, which is suppressed by further mutating the zmm msh5. This suggests that in the absence of MutLγ, recombination intermediates produced by ZMMs are resolved by MUS81, which does not ensure CO formation. Finally, CO interference is marginally affected in mlh1, which is compatible with a random sub-sampling of normally patterned CO sites. We conclude that AtMutLγ imposes designated recombination intermediates to be resolved exclusively as COs, supporting the view that MutLγ asymmetrically resolves double-Holliday junctions, yielding COs.

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