Yerkin Dunbayev (IBS, UNIST) | 한빛사논문 > 한빛사

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IBS, UNIST

Nucleic Acids Res., 29 April 2026, gkag332 | https://doi.org/10.1093/nar/gkag332 The DNA helicase HELQ promotes replication fork reversal in coordination with BRCA2- and FANCD2-mediated repair pathways

Yerkin Dunbayev^1,2,†, Yen-Ju Chen^3,†, Lorenzo Sassi^4,5, Eun A Lee¹, Jae Sun Ra¹, Moonjung Choi¹, Anirban Mukherjee⁶, Karen M. Vasquez⁶, Vincenzo Costanzo^4,5, Peter Chi^3,7,*, Kei-ichi Takata^1,8,*

¹Center for Genomic Integrity, Institute for Basic Science, Ulsan 44919, Republic of Korea
²Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
³Institute of Biochemical Sciences, National Taiwan University, Taipei 10617, Taiwan
⁴Department of Oncology and Hematology-Oncology, University of Milan, Via Adamello 16, Milan 20139, Italy
⁵IFOM-ETS, The AIRC Institute of Molecular Oncology, Milan 20139, Italy
⁶Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Boulevard, Austin, TX 78723, United States
⁷Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan
⁸Department of Biomedical Engineering, College of Information-Bio Convergence Engineering, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea

^∗To whom correspondence should be addressed. : Kei-ichi Takata
Correspondence may also be addressed to Peter Chi.
^†The first two authors should be regarded as Joint First Authors.

Abstract

HELQ is a 3′–5′ DNA helicase whose loss sensitizes cells to DNA-damaging agents, particularly DNA crosslinkers. HELQ interacts with the RAD51 paralog complex RAD51B–RAD51C–RAD51D–XRCC2 (BCDX2), a key mediator of replication fork reversal. Using DNA fiber assays, we show that HELQ and BCDX2 act epistatically to slow replication fork progression under replication stress. Because fork reversal transiently regresses nascent strands into a four-way junction and reduces net DNA synthesis, this fork slowing provides a functional readout of fork reversal. Directly supporting this model, electron microscopy reveals that reversed fork structures are reduced in HELQ-knockout cells. Consistent with a role in fork reversal, HELQ deletion suppresses nascent strand degradation when BRCA2- or FANCD2-dependent fork protection is lost. Mechanistically, biochemical reconstitution shows that HELQ is stimulated by RPA on fork substrates containing a leading strand gap, and these findings are consistent with the cell-based DNA fiber assays. Together, these results identify HELQ as a specialized regulator of replication fork remodeling that promotes fork reversal through the BCDX2 pathway.

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