SLX4 dampens MutSα-dependent mismatch repair

ABSTRACTThe tumour suppressor SLX4 plays multiple roles in the maintenance of genome stability, acting as a scaffold for structure-specific endonucleases and other DNA repair proteins. It directly interacts with the mismatch repair (MMR) protein MSH2 but the significance of this interaction remained unknown until recent findings showing that MutSβ (MSH2-MSH3) stimulates in vitro the SLX4-dependent Holliday junction resolvase activity. Here, we characterize the mode of interaction between SLX4 and MSH2, which relies on an MSH2-interacting peptide (SHIP box) that drives interaction of SLX4 with both MutSβ and MutSα (MSH2-MSH6). While we show that this MSH2 binding domain is dispensable for the well-established role of SLX4 in interstrand crosslink repair, we find that it mediates inhibition of MutSα-dependent MMR by SLX4, unravelling an unanticipated function of SLX4.

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Candida albicans forms biofilms on the vaginal mucosa

Microbiology ◽

10.1099/mic.0.039354-0 ◽

2010 ◽

Vol 156 (12) ◽

pp. 3635-3644 ◽

Cited By ~ 168

Author(s):

M. M. Harriott ◽

E. A. Lilly ◽

T. E. Rodriguez ◽

P. L. Fidel ◽

M. C. Noverr

Keyword(s):

Biofilm Formation ◽

Ex Vivo ◽

Microscopic Analysis ◽

Vaginal Mucosa ◽

First Time ◽

Established Role ◽

Type Strains

Current understanding of resistance and susceptibility to vulvovaginal candidiasis challenges existing paradigms of host defence against fungal infection. While abiotic biofilm formation has a clearly established role during systemic Candida infections, it is not known whether C. albicans forms biofilms on the vaginal mucosa and the possible role of biofilms in disease. In vivo and ex vivo murine vaginitis models were employed to examine biofilm formation by scanning electron and confocal microscopy. C. albicans strains included 3153A (lab strain), DAY185 (parental control strain), and mutants defective in morphogenesis and/or biofilm formation in vitro (efg1/efg1 and bcr1/bcr1). Both 3153A and DAY815 formed biofilms on the vaginal mucosa in vivo and ex vivo as indicated by high fungal burden and microscopic analysis demonstrating typical biofilm architecture and presence of extracellular matrix (ECM) co-localized with the presence of fungi. In contrast, efg1/efg1 and bcr1/bcr1 mutant strains exhibited weak or no biofilm formation/ECM production in both models compared to wild-type strains and complemented mutants despite comparable colonization levels. These data show for the first time that C. albicans forms biofilms in vivo on vaginal epithelium, and that in vivo biotic biofilm formation requires regulators of biofilm formation (BCR1) and morphogenesis (EFG1).

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RNA Interference Inhibition of Mus81 Reduces Mitotic Recombination in Human Cells

Molecular Biology of the Cell ◽

10.1091/mbc.e03-08-0580 ◽

2004 ◽

Vol 15 (2) ◽

pp. 552-562 ◽

Cited By ~ 32

Author(s):

Veronique Blais ◽

Hui Gao ◽

Cherilyn A. Elwell ◽

Michael N. Boddy ◽

Pierre-Henri L. Gaillard ◽

...

Keyword(s):

Rna Interference ◽

Direct Evidence ◽

Mitotic Recombination ◽

Holliday Junctions ◽

Replication Forks ◽

Holliday Junction Resolvase ◽

Substrate Cleavage

Mus81 is a highly conserved endonuclease with homology to the XPF subunit of the XPF-ERCC1 complex. In yeast Mus81 associates with a second subunit, Eme1 or Mms4, which is essential for endonuclease activity in vitro and for in vivo function. Human Mus81 binds to a homolog of fission yeast Eme1 in vitro and in vivo. We show that recombinant Mus81-Eme1 cleaves replication forks, 3′ flap substrates, and Holliday junctions in vitro. By use of differentially tagged versions of Mus81 and Eme1, we find that Mus81 associates with Mus81 and that Eme1 associates with Eme1. Thus, complexes containing two or more Mus81-Eme1 units could function to coordinate substrate cleavage in vivo. Down-regulation of Mus81 by RNA interference reduces mitotic recombination in human somatic cells. The recombination defect is rescued by expression of a bacterial Holliday junction resolvase. These data provide direct evidence for a role of Mus81-Eme1 in mitotic recombination in higher eukaryotes and support the hypothesis that Mus81-Eme1 resolves Holliday junctions in vivo.

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Mismatch Repair: From Preserving Genome Stability to Enabling Mutation Studies in Real-Time Single Cells

Cells ◽

10.3390/cells10061535 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1535

Author(s):

Marina Elez

Keyword(s):

Real Time ◽

Mismatch Repair ◽

Genetic Information ◽

Genome Stability ◽

Direct Evidence ◽

Single Cells ◽

Living Cells ◽

Spontaneous Mutations ◽

Mismatch Recognition

Mismatch Repair (MMR) is an important and conserved keeper of the maintenance of genetic information. Miroslav Radman’s contributions to the field of MMR are multiple and tremendous. One of the most notable was to provide, along with Bob Wagner and Matthew Meselson, the first direct evidence for the existence of the methyl-directed MMR. The purpose of this review is to outline several aspects and biological implications of MMR that his work has helped unveil, including the role of MMR during replication and recombination editing, and the current understanding of its mechanism. The review also summarizes recent discoveries related to the visualization of MMR components and discusses how it has helped shape our understanding of the coupling of mismatch recognition to replication. Finally, the author explains how visualization of MMR components has paved the way to the study of spontaneous mutations in living cells in real time.

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Current Understanding of the Role of PPARγin Gastrointestinal Cancers

PPAR Research ◽

10.1155/2009/816957 ◽

2009 ◽

Vol 2009 ◽

pp. 1-8 ◽

Cited By ~ 7

Author(s):

Bing Zou ◽

Liang Qiao ◽

Benjamin C. Y. Wong

Keyword(s):

Antitumor Effect ◽

Cell Cycle Control ◽

Control Cell ◽

Multiple Roles ◽

Gastrointestinal Cancers ◽

Recent Developments ◽

Positive Results ◽

Prevention And Therapy

Numerous studies have indicated that PPARγplays multiple roles such as in inflammation, cell cycle control, cell proliferation, apoptosis, and carcinogenesis, thus PPARγcontributes to the homeostasis. Many in vitro studies have showed that ligand-induced activation of PPARγpossess antitumor effect in many cancers including CRC. However, the role of PPARγin gastrointestinal cancers, especially in colorectal cancer, is rather controversial. Nevertheless, some recent studies with the positive results on the possible application of PPARγligands, such as Bezafibrate or Rosiglitazone in gastrointestinal cancers, have suggested a potential usefulness of PPARγagonists in cancer prevention and therapy. In this review, the authors discuss the recent developments in the role of PPARγin gastrointestinal cancers.

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Multiple roles of ERCC1-XPF in mammalian interstrand crosslink repair

Environmental and Molecular Mutagenesis ◽

10.1002/em.20583 ◽

2010 ◽

pp. n/a-n/a ◽

Cited By ~ 7

Author(s):

Jennifer J. Rahn ◽

Gerald M. Adair ◽

Rodney S. Nairn

Keyword(s):

Multiple Roles ◽

Interstrand Crosslink ◽

Interstrand Crosslink Repair ◽

Crosslink Repair

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The yeast Hrq1 helicase stimulates Pso2 translesion nuclease activity and thereby promotes DNA interstrand crosslink repair

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013626 ◽

2020 ◽

Vol 295 (27) ◽

pp. 8945-8957 ◽

Cited By ~ 3

Author(s):

Cody M. Rogers ◽

Chun-Ying Lee ◽

Samuel Parkins ◽

Nicholas J. Buehler ◽

Sabine Wenzel ◽

...

Keyword(s):

Single Molecule ◽

Nuclease Activity ◽

Dna Lesions ◽

Principal Mechanism ◽

Single Molecule Fret ◽

Interstrand Crosslink ◽

Physical Barriers ◽

A Site ◽

Interstrand Crosslink Repair

DNA interstrand crosslink (ICL) repair requires a complex network of DNA damage response pathways. Removal of the ICL lesions is vital, as they are physical barriers to essential DNA processes that require the separation of duplex DNA, such as replication and transcription. The Fanconi anemia (FA) pathway is the principal mechanism for ICL repair in metazoans and is coupled to DNA replication. In Saccharomyces cerevisiae, a vestigial FA pathway is present, but ICLs are predominantly repaired by a pathway involving the Pso2 nuclease, which is hypothesized to use its exonuclease activity to digest through the lesion to provide access for translesion polymerases. However, Pso2 lacks translesion nuclease activity in vitro, and mechanistic details of this pathway are lacking, especially relative to FA. We recently identified the Hrq1 helicase, a homolog of the disease-linked enzyme RecQ-like helicase 4 (RECQL4), as a component of Pso2-mediated ICL repair. Here, using genetic, biochemical, and biophysical approaches, including single-molecule FRET (smFRET)– and gel-based nuclease assays, we show that Hrq1 stimulates the Pso2 nuclease through a mechanism that requires Hrq1 catalytic activity. Importantly, Hrq1 also stimulated Pso2 translesion nuclease activity through a site-specific ICL in vitro. We noted that stimulation of Pso2 nuclease activity is specific to eukaryotic RecQ4 subfamily helicases, and genetic and biochemical data suggest that Hrq1 likely interacts with Pso2 through their N-terminal domains. These results advance our understanding of FA-independent ICL repair and establish a role for the RecQ4 helicases in the repair of these detrimental DNA lesions.

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A single cycle of treatment with temozolomide, alone or combined with O6-benzylguanine, induces strong chemoresistance in melanoma cell clones in vitro: role of O6-methylguanine-DNA methyltransferase and the mismatch repair system

International Journal of Oncology ◽

10.3892/ijo.29.4.785 ◽

2006 ◽

Author(s):

Ester Alvino ◽

Daniele Castiglia ◽

Simona Caporali ◽

Rita Pepponi ◽

Patrizia Caporaso ◽

...

Keyword(s):

Mismatch Repair ◽

Melanoma Cell ◽

Dna Methyltransferase ◽

Repair System ◽

Single Cycle ◽

Methylguanine Dna Methyltransferase ◽

Cell Clones ◽

Mismatch Repair System

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Fanconi anemia pathway and its relationship with cancer

Genome Instability & Disease ◽

10.1007/s42764-021-00043-0 ◽

2021 ◽

Author(s):

Chenchen Dan ◽

Hongjing Pei ◽

Buzhe Zhang ◽

Xuan Zheng ◽

Dongmei Ran ◽

...

Keyword(s):

Fanconi Anemia ◽

Genome Stability ◽

Excision Repair ◽

Cancer Therapies ◽

Repair Pathway ◽

Hematological Disease ◽

Interstrand Crosslink ◽

Nucleotide Excision ◽

Associated Proteins

AbstractFanconi Anemia (FA) is a rare inherited hematological disease, caused by mutations in genes involved in the DNA interstrand crosslink (ICL) repair. Up to date, 22 genes have been identified that encode a series of functionally associated proteins that recognize ICL lesion and mediate the activation of the downstream DNA repair pathway including nucleotide excision repair, translesion synthesis, and homologous recombination. The FA pathway is strictly regulated by complex mechanisms such as ubiquitination, phosphorylation, and degradation signals that are essential for the maintenance of genome stability. Here, we summarize the discovery history and recent advances of the FA genes, and further discuss the role of FA pathway in carcinogenesis and cancer therapies.

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Mitotic crossovers between diverged sequences are regulated by mismatch repair proteins in Saccaromyces cerevisiae.

Molecular and Cellular Biology ◽

10.1128/mcb.16.3.1085 ◽

1996 ◽

Vol 16 (3) ◽

pp. 1085-1093 ◽

Cited By ~ 128

Author(s):

A Datta ◽

A Adjiri ◽

L New ◽

G F Crouse ◽

S Jinks Robertson

Keyword(s):

Mismatch Repair ◽

Genome Stability ◽

Multiple Roles ◽

Homologous Sequences ◽

Mismatch Repair Proteins ◽

Repair Systems ◽

The Stability ◽

Saccaromyces Cerevisiae ◽

Simple Repeats ◽

Repair Genes

Mismatch repair systems correct replication- and recombination-associated mispaired bases and influence the stability of simple repeats. These systems thus serve multiple roles in maintaining genetic stability in eukaryotes, and human mismatch repair defects have been associated with hereditary predisposition to cancer. In prokaryotes, mismatch repair systems also have been shown to limit recombination between diverged (homologous) sequences. We have developed a unique intron-based assay system to examine the effects of yeast mismatch repair genes (PMS1, MSH2, and MSH3) on crossovers between homologous sequences. We find that the apparent antirecombination effects of mismatch repair proteins in mitosis are related to the degree of substrate divergence. Defects in mismatch repair can elevate homologous recombination between 91% homologous substrates as much as 100-fold while having only modest effects on recombination between 77% homologous substrates. These observations have implications for genome stability and general mechanisms of recombination in eukaryotes.

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