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

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.

doi:10.1038/ncomms15855

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

Journal Article · Tue Jun 27 00:00:00 EDT 2017 · Nature Communications

DOI:https://doi.org/10.1038/ncomms15855· OSTI ID:1408438

Tsutakawa, Susan E. ^[1]; Thompson, Mark J. ^[2]; Arvai, Andrew S. ^[3]; Neil, Alexander J. ^[4]; Shaw, Steven J. ^[2]; Algasaier, Sana I. ^[2]; Kim, Jane C. ^[4]; Finger, L. David ^[2]; Jardine, Emma ^[2]; Gotham, Victoria J. B. ^[2];

^[5]; Her, Mai Z. ^[1]; Rashid, Fahad ^[6];

^[6]; Mirkin, Sergei M. ^[4]; Grasby, Jane A. ^[2];

^[7]

Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Univ. of Sheffield (United Kingdom). Centre for Chemical Biology, Sheffield Inst. for Nucleic Acids (SInFoNiA), Dept. of Chemistry
Scripps Research Inst., La Jolla, CA (United States). Dept. of Molecular Biology
Tufts Univ., Medford, MA (United States). Dept. of Biology
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering
King Abdullah Univ. of Science and Technology, Thuwal (Saudi Arabia). Division of Biological and Environmental Sciences and Engineering
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. of Texas, Houston, TX (United States). Dept. of Molecular and Cellular Oncology

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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-05CH11231; AC02-76SF00515

OSTI ID:: 1408438

Journal Information:: Nature Communications, Vol. 8; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 68 works

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