Phosphate steering by Flap Endonuclease 1 promotes 5′-flap specificity and incision to prevent genome instability

DNA replication and repair enzyme Flap Endonuclease 1 (FEN1) is vital for genome integrity, and FEN1 mutations arise in multiple cancers. FEN1 precisely cleaves single-stranded (ss) 5′-flaps one nucleotide into duplex (ds) DNA. Yet, how FEN1 selects for but does not incise the ss 5′-flap was enigmat...

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Published inNature communications Vol. 8; no. 1; pp. 15855 - 15
Main Authors Tsutakawa, Susan E., Thompson, Mark J., Arvai, Andrew S., Neil, Alexander J., Shaw, Steven J., Algasaier, Sana I., Kim, Jane C., Finger, L. David, Jardine, Emma, Gotham, Victoria J.B., Sarker, Altaf H., Her, Mai Z., Rashid, Fahad, Hamdan, Samir M., Mirkin, Sergei M., Grasby, Jane A., Tainer, John A.
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 27.06.2017
Nature Publishing Group
Nature Portfolio
Subjects
60 APPLIED LIFE SCIENCES
631/208/211
631/45/147
631/45/173
631/535/1266
Amino Acid Sequence
BASIC BIOLOGICAL SCIENCES
Binding Sites
Biochemistry
Catalysis
Catalytic Domain
Crystallography
Deoxyribonucleic acid
DNA
DNA - chemistry
DNA - genetics
DNA - metabolism
DNA biosynthesis
DNA Repair
DNA Replication
Electrostatic properties
Endonuclease
FEN1 protein
Flap Endonucleases - chemistry
Flap Endonucleases - genetics
Flap Endonucleases - metabolism
Flaps
Genomes
Genomic Instability
Humanities and Social Sciences
Humans
In vitro methods and tests
Integrity
multidisciplinary
Mutation
Phosphate
Phosphates - chemistry
Phosphates - metabolism
Polarity
Replication
Residues
Science
Science (multidisciplinary)
Sequence Alignment
Stability
Steering
Substrate Specificity
Online AccessGet full text

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Abstract DNA replication and repair enzyme Flap Endonuclease 1 (FEN1) is vital for genome integrity, and FEN1 mutations arise in multiple cancers. FEN1 precisely cleaves single-stranded (ss) 5′-flaps one nucleotide into duplex (ds) DNA. Yet, how FEN1 selects for but does not incise the ss 5′-flap was enigmatic. Here we combine crystallographic, biochemical and genetic analyses to show that two dsDNA binding sites set the 5′polarity and to reveal unexpected control of the DNA phosphodiester backbone by electrostatic interactions. Via ‘phosphate steering’, basic residues energetically steer an inverted ss 5′-flap through a gateway over FEN1’s active site and shift dsDNA for catalysis. Mutations of these residues cause an 18,000-fold reduction in catalytic rate in vitro and large-scale trinucleotide (GAA) n repeat expansions in vivo , implying failed phosphate-steering promotes an unanticipated lagging-strand template-switch mechanism during replication. Thus, phosphate steering is an unappreciated FEN1 function that enforces 5′-flap specificity and catalysis, preventing genomic instability. Flap Endonuclease 1 is a DNA replication and repair enzyme indispensable for maintaining genomic stability. Here the authors provide mechanistic details on how FEN1 selects for 5′-flaps and promotes catalysis to avoid large-scale repeat expansion by a process termed ‘phosphate steering’.
AbstractList Flap Endonuclease 1 is a DNA replication and repair enzyme indispensable for maintaining genomic stability. Here the authors provide mechanistic details on how FEN1 selects for 5′-flaps and promotes catalysis to avoid large-scale repeat expansion by a process termed ‘phosphate steering’.
DNA replication and repair enzyme Flap Endonuclease 1 (FEN1) is vital for genome integrity, and FEN1 mutations arise in multiple cancers. FEN1 precisely cleaves single-stranded (ss) 5′-flaps one nucleotide into duplex (ds) DNA. Yet, how FEN1 selects for but does not incise the ss 5′-flap was enigmatic. Here we combine crystallographic, biochemical and genetic analyses to show that two dsDNA binding sites set the 5′polarity and to reveal unexpected control of the DNA phosphodiester backbone by electrostatic interactions. Via ‘phosphate steering’, basic residues energetically steer an inverted ss 5′-flap through a gateway over FEN1’s active site and shift dsDNA for catalysis. Mutations of these residues cause an 18,000-fold reduction in catalytic rate in vitro and large-scale trinucleotide (GAA) n repeat expansions in vivo , implying failed phosphate-steering promotes an unanticipated lagging-strand template-switch mechanism during replication. Thus, phosphate steering is an unappreciated FEN1 function that enforces 5′-flap specificity and catalysis, preventing genomic instability. Flap Endonuclease 1 is a DNA replication and repair enzyme indispensable for maintaining genomic stability. Here the authors provide mechanistic details on how FEN1 selects for 5′-flaps and promotes catalysis to avoid large-scale repeat expansion by a process termed ‘phosphate steering’.
DNA replication and repair enzyme Flap Endonuclease 1 (FEN1) is vital for genome integrity, and FEN1 mutations arise in multiple cancers. FEN1 precisely cleaves single-stranded (ss) 5'-flaps one nucleotide into duplex (ds) DNA. Yet, how FEN1 selects for but does not incise the ss 5'-flap was enigmatic. Here we combine crystallographic, biochemical and genetic analyses to show that two dsDNA binding sites set the 5'polarity and to reveal unexpected control of the DNA phosphodiester backbone by electrostatic interactions. Via 'phosphate steering', basic residues energetically steer an inverted ss 5'-flap through a gateway over FEN1's active site and shift dsDNA for catalysis. Mutations of these residues cause an 18,000-fold reduction in catalytic rate in vitro and large-scale trinucleotide (GAA)n repeat expansions in vivo, implying failed phosphate-steering promotes an unanticipated lagging-strand template-switch mechanism during replication. Thus, phosphate steering is an unappreciated FEN1 function that enforces 5'-flap specificity and catalysis, preventing genomic instability.DNA replication and repair enzyme Flap Endonuclease 1 (FEN1) is vital for genome integrity, and FEN1 mutations arise in multiple cancers. FEN1 precisely cleaves single-stranded (ss) 5'-flaps one nucleotide into duplex (ds) DNA. Yet, how FEN1 selects for but does not incise the ss 5'-flap was enigmatic. Here we combine crystallographic, biochemical and genetic analyses to show that two dsDNA binding sites set the 5'polarity and to reveal unexpected control of the DNA phosphodiester backbone by electrostatic interactions. Via 'phosphate steering', basic residues energetically steer an inverted ss 5'-flap through a gateway over FEN1's active site and shift dsDNA for catalysis. Mutations of these residues cause an 18,000-fold reduction in catalytic rate in vitro and large-scale trinucleotide (GAA)n repeat expansions in vivo, implying failed phosphate-steering promotes an unanticipated lagging-strand template-switch mechanism during replication. Thus, phosphate steering is an unappreciated FEN1 function that enforces 5'-flap specificity and catalysis, preventing genomic instability.
DNA replication and repair enzyme Flap Endonuclease 1 (FEN1) is vital for genome integrity, and FEN1 mutations arise in multiple cancers. FEN1 precisely cleaves single-stranded (ss) 5'-flaps one nucleotide into duplex (ds) DNA. Yet, how FEN1 selects for but does not incise the ss 5'-flap was enigmatic. Here we combine crystallographic, biochemical and genetic analyses to show that two dsDNA binding sites set the 5'polarity and to reveal unexpected control of the DNA phosphodiester backbone by electrostatic interactions. Via phosphate steering', basic residues energetically steer an inverted ss 5'-flap through a gateway over FEN1's active site and shift dsDNA for catalysis. Mutations of these residues cause an 18,000-fold reduction in catalytic rate in vitro and large-scale trinucleotide (GAA)n repeat expansions in vivo, implying failed phosphate-steering promotes an unanticipated lagging-strand template-switch mechanism during replication. Thus, phosphate steering is an unappreciated FEN1 function that enforces 5'-flap specificity and catalysis, preventing genomic instability.
DNA replication and repair enzyme Flap Endonuclease 1 (FEN1) is vital for genome integrity, and FEN1 mutations arise in multiple cancers. FEN1 precisely cleaves single-stranded (ss) 5′-flaps one nucleotide into duplex (ds) DNA. Yet, how FEN1 selects for but does not incise the ss 5′-flap was enigmatic. Here we combine crystallographic, biochemical and genetic analyses to show that two dsDNA binding sites set the 5′polarity and to reveal unexpected control of the DNA phosphodiester backbone by electrostatic interactions. Via ‘phosphate steering’, basic residues energetically steer an inverted ss 5′-flap through a gateway over FEN1’s active site and shift dsDNA for catalysis. Mutations of these residues cause an 18,000-fold reduction in catalytic rate in vitro and large-scale trinucleotide (GAA) n repeat expansions in vivo , implying failed phosphate-steering promotes an unanticipated lagging-strand template-switch mechanism during replication. Thus, phosphate steering is an unappreciated FEN1 function that enforces 5′-flap specificity and catalysis, preventing genomic instability.
DNA replication and repair enzyme Flap Endonuclease 1 (FEN1) is vital for genome integrity, and FEN1 mutations arise in multiple cancers. FEN1 precisely cleaves single-stranded (ss) 5'-flaps one nucleotide into duplex (ds) DNA. Yet, how FEN1 selects for but does not incise the ss 5'-flap was enigmatic. Here we combine crystallographic, biochemical and genetic analyses to show that two dsDNA binding sites set the 5'polarity and to reveal unexpected control of the DNA phosphodiester backbone by electrostatic interactions. Via 'phosphate steering', basic residues energetically steer an inverted ss 5'-flap through a gateway over FEN1's active site and shift dsDNA for catalysis. Mutations of these residues cause an 18,000-fold reduction in catalytic rate in vitro and large-scale trinucleotide (GAA) repeat expansions in vivo, implying failed phosphate-steering promotes an unanticipated lagging-strand template-switch mechanism during replication. Thus, phosphate steering is an unappreciated FEN1 function that enforces 5'-flap specificity and catalysis, preventing genomic instability.
ArticleNumber 15855
Author Thompson, Mark J.
Algasaier, Sana I.
Her, Mai Z.
Gotham, Victoria J.B.
Hamdan, Samir M.
Neil, Alexander J.
Rashid, Fahad
Kim, Jane C.
Finger, L. David
Tsutakawa, Susan E.
Shaw, Steven J.
Sarker, Altaf H.
Arvai, Andrew S.
Tainer, John A.
Mirkin, Sergei M.
Grasby, Jane A.
Jardine, Emma
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/28653660$$D View this record in MEDLINE/PubMed
https://www.osti.gov/servlets/purl/1408438$$D View this record in Osti.gov
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ContentType Journal Article
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National Institutes of Health (NIH)
AC02-05CH11231; AC02-76SF00515
USDOE Office of Science (SC), Biological and Environmental Research (BER)
These authors contributed equally to this work.
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Snippet DNA replication and repair enzyme Flap Endonuclease 1 (FEN1) is vital for genome integrity, and FEN1 mutations arise in multiple cancers. FEN1 precisely...
Flap Endonuclease 1 is a DNA replication and repair enzyme indispensable for maintaining genomic stability. Here the authors provide mechanistic details on how...
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SubjectTerms 60 APPLIED LIFE SCIENCES
631/208/211
631/45/147
631/45/173
631/535/1266
Amino Acid Sequence
BASIC BIOLOGICAL SCIENCES
Binding Sites
Biochemistry
Catalysis
Catalytic Domain
Crystallography
Deoxyribonucleic acid
DNA
DNA - chemistry
DNA - genetics
DNA - metabolism
DNA biosynthesis
DNA Repair
DNA Replication
Electrostatic properties
Endonuclease
FEN1 protein
Flap Endonucleases - chemistry
Flap Endonucleases - genetics
Flap Endonucleases - metabolism
Flaps
Genomes
Genomic Instability
Humanities and Social Sciences
Humans
In vitro methods and tests
Integrity
multidisciplinary
Mutation
Phosphate
Phosphates - chemistry
Phosphates - metabolism
Polarity
Replication
Residues
Science
Science (multidisciplinary)
Sequence Alignment
Stability
Steering
Substrate Specificity
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Title Phosphate steering by Flap Endonuclease 1 promotes 5′-flap specificity and incision to prevent genome instability
URI https://link.springer.com/article/10.1038/ncomms15855
https://www.ncbi.nlm.nih.gov/pubmed/28653660
https://www.proquest.com/docview/1913787827
https://www.proquest.com/docview/1914291641
https://www.osti.gov/servlets/purl/1408438
https://pubmed.ncbi.nlm.nih.gov/PMC5490271
https://doaj.org/article/7d8f8666ae664b27be8155fb17c1e260
Volume 8
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