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: Ján Tkáč, Guotai Xu, Hemanta Adhikary, Jordan T F Young, David Gallo, Cristina Escribano-Díaz, Jana Krietsch, Alexandre Orthwein, Meagan Munro, Wendy Sol, Abdallah Al-Hakim, Zhen-Yuan Lin, Jos Jonkers, Piet Borst, Grant W Brown, Anne-Claude Gingras, Sven Rottenberg, Jean-Yves Masson, Daniel Durocher
• Journal: Molecular cell (Mol Cell) Vol. 61 Issue 3 Pg. 405-418 (Feb 04 2016) ISSN: 1097-4164 [Electronic] United States
• PMID: 26774285 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• BRCA1 Protein
• BRCA1 protein, human
• Brca1 protein, mouse
• Phthalazines
• Piperazines
• Poly(ADP-ribose) Polymerase Inhibitors
• Tumor Suppressor Proteins
• EXO1 protein, human
• Exo1 protein, mouse
• Exodeoxyribonucleases
• Bloom syndrome protein
• HELB protein, human
• Helb protein, mouse
• DNA Helicases
• DNA2 protein, human
• RecQ Helicases
• DNA Repair Enzymes
• olaparib

Topics

• Animals
• BRCA1 Protein (genetics)
• DNA End-Joining Repair
• DNA Helicases (deficiency, genetics, metabolism)
• DNA Repair Enzymes (genetics, metabolism)
• Exodeoxyribonucleases (genetics, metabolism)
• Feedback, Physiological
• Female
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• HeLa Cells
• Humans
• Mammary Neoplasms, Experimental (drug therapy, enzymology, genetics, pathology)
• Mice
• Mice, 129 Strain
• Mice, Inbred C57BL
• Mice, Knockout
• Phthalazines (pharmacology)
• Piperazines (pharmacology)
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology)
• RNA Interference
• RecQ Helicases (genetics, metabolism)
• S Phase
• Time Factors
• Transfection
• Tumor Suppressor Proteins (genetics)