title: HELB Is a Feedback Inhibitor of DNA End Resection.
abstract: DNA double-strand break repair by homologous recombination is initiated by the formation of 3' single-stranded DNA (ssDNA) overhangs by a process termed end resection. Although much focus has been given to the decision to initiate resection, little is known of the mechanisms that regulate the ongoing formation of ssDNA tails. Here we report that DNA helicase B (HELB) underpins a feedback inhibition mechanism that curtails resection. HELB is recruited to ssDNA by interacting with RPA and uses its 5'-3' ssDNA translocase activity to inhibit EXO1 and BLM-DNA2, the nucleases catalyzing resection. HELB acts independently of 53BP1 and is exported from the nucleus as cells approach S phase, concomitant with the upregulation of resection. Consistent with its role as a resection antagonist, loss of HELB results in PARP inhibitor resistance in BRCA1-deficient tumor cells. We conclude that mammalian DNA end resection triggers its own inhibition via the recruitment of HELB.
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, ON M5S 1A8, Canada.
authors.forename: Ján
authors.initials: J
authors.lastname: Tkáč
authors.affiliation: Division of Molecular Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Guotai
authors.initials: G
authors.lastname: Xu
authors.affiliation: Genome Stability Laboratory, CHU de Québec Research Center, HDQ Pavilion, Oncology Axis, 9 McMahon, Québec City, QC G1R 2J6, Canada; Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Québec City, QC G1V 0A6, Canada.
authors.forename: Hemanta
authors.initials: H
authors.lastname: Adhikary
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, ON M5S 1A8, Canada.
authors.forename: Jordan T F
authors.initials: JTF
authors.lastname: Young
authors.affiliation: Department of Biochemistry and Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, ON M5S 3E1, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Gallo
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
authors.forename: Cristina
authors.initials: C
authors.lastname: Escribano-Díaz
authors.affiliation: Genome Stability Laboratory, CHU de Québec Research Center, HDQ Pavilion, Oncology Axis, 9 McMahon, Québec City, QC G1R 2J6, Canada; Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Québec City, QC G1V 0A6, Canada.
authors.forename: Jana
authors.initials: J
authors.lastname: Krietsch
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Orthwein
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
authors.forename: Meagan
authors.initials: M
authors.lastname: Munro
authors.affiliation: Division of Molecular Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Wendy
authors.initials: W
authors.lastname: Sol
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
authors.forename: Abdallah
authors.initials: A
authors.lastname: Al-Hakim
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
authors.forename: Zhen-Yuan
authors.initials: ZY
authors.lastname: Lin
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.affiliation: Division of Molecular Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Piet
authors.initials: P
authors.lastname: Borst
authors.affiliation: Department of Biochemistry and Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, ON M5S 3E1, Canada.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Brown
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, ON M5S 1A8, Canada.
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gingras
authors.affiliation: Division of Molecular Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Laenggasstrasse 122, 3012 Bern, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Rottenberg
authors.affiliation: Genome Stability Laboratory, CHU de Québec Research Center, HDQ Pavilion, Oncology Axis, 9 McMahon, Québec City, QC G1R 2J6, Canada; Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Québec City, QC G1V 0A6, Canada.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Masson
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, ON M5S 1A8, Canada. Electronic address: durocher@lunenfeld.ca.
authors.forename: Daniel
authors.initials: D
authors.lastname: Durocher
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics; D059766:DNA End-Joining Repair; D004265:DNA Helicases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism; D016196:S Phase; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C000605931:Brca1 protein, mouse; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D025521:Tumor Suppressor Proteins; C114331:EXO1 protein, human; C583623:Exo1 protein, mouse; D005090:Exodeoxyribonucleases; C097151:Bloom syndrome protein; C484263:HELB protein, human; C484264:Helb protein, mouse; D004265:DNA Helicases; C509908:DNA2 protein, human; D053484:RecQ Helicases; D045643:DNA Repair Enzymes; C531550:olaparib