During cell division, DNA replication faces constant threats from interstrand crosslinks (ICLs) that chemically fuse DNA strands, halting the replication machinery. These lesions occur naturally but also result from chemotherapy drugs like cisplatin and mitomycin C. Without proper management, stalled replication forks collapse, causing DNA breakage and cell death.
A team led by Kei-ichi TAKATA at the IBS Center for Genomic Integrity demonstrates that the DNA helicase HELQ protects cells by promoting replication fork remodeling. When replication forks—forming Y-shaped structures—encounter ICLs, they stall abruptly. HELQ triggers fork reversal, restructuring the three-way junction into a stable four-way configuration that allows time for repair.
DNA fiber analysis showed normal cells slow replication when treated with crosslinking agents, indicating successful fork reversal. HELQ-deficient cells failed this protective slowdown. Electron microscopy confirmed far fewer reversed forks in HELQ-lacking cells under replication stress.
HELQ functions as an active molecular motor at stalled sites, using its enzymatic activity to reshape DNA structures. A helicase-inactive HELQ mutant abolished replication slowing under damage, proving catalytic activity is essential. HELQ works with the BCDX2 DNA repair complex in the same pathway to facilitate reversal.
Previous studies documented HELQ-deficient cells' hypersensitivity to crosslinking agents without mechanistic insight. This research shows failed fork stabilization causes damage accumulation and toxicity. Without HELQ, cells rely on error-prone repair pathways, increasing mutations and compromising genome integrity.
These findings, published in Nucleic Acids Research, hold relevance for cancer therapy, where crosslinking agents remain chemotherapy mainstays. HELQ activity differences may influence tumor sensitivity or resistance. "This study explains why HELQ-deficient cells are highly sensitive to DNA crosslinking agents," said Director MYUNG Kyungjae. "By showing that HELQ directly promotes replication fork reversal, we now have a clearer picture of how cells protect their genomes against one of the most toxic forms of DNA damage."
Publication details: Yerkin Dunbayev, Yen-Ju Chen, Lorenzo Sassi, Eun A Lee, Jae Sun Ra, Moonjung Choi, Anirban Mukherjee, Karen M Vasquez, Vincenzo Costanzo, Peter Chi, Kei-ichi Takata, The DNA helicase HELQ promotes replication fork reversal in coordination with BRCA2- and FANCD2-mediated repair pathways, Nucleic Acids Research, Volume 54, Issue 8, 8 May 2026, gkag332, https://doi.org/10.1093/nar/gkag332
A team led by Kei-ichi TAKATA at the IBS Center for Genomic Integrity demonstrates that the DNA helicase HELQ protects cells by promoting replication fork remodeling. When replication forks—forming Y-shaped structures—encounter ICLs, they stall abruptly. HELQ triggers fork reversal, restructuring the three-way junction into a stable four-way configuration that allows time for repair.
DNA fiber analysis showed normal cells slow replication when treated with crosslinking agents, indicating successful fork reversal. HELQ-deficient cells failed this protective slowdown. Electron microscopy confirmed far fewer reversed forks in HELQ-lacking cells under replication stress.
HELQ functions as an active molecular motor at stalled sites, using its enzymatic activity to reshape DNA structures. A helicase-inactive HELQ mutant abolished replication slowing under damage, proving catalytic activity is essential. HELQ works with the BCDX2 DNA repair complex in the same pathway to facilitate reversal.
Previous studies documented HELQ-deficient cells' hypersensitivity to crosslinking agents without mechanistic insight. This research shows failed fork stabilization causes damage accumulation and toxicity. Without HELQ, cells rely on error-prone repair pathways, increasing mutations and compromising genome integrity.
These findings, published in Nucleic Acids Research, hold relevance for cancer therapy, where crosslinking agents remain chemotherapy mainstays. HELQ activity differences may influence tumor sensitivity or resistance. "This study explains why HELQ-deficient cells are highly sensitive to DNA crosslinking agents," said Director MYUNG Kyungjae. "By showing that HELQ directly promotes replication fork reversal, we now have a clearer picture of how cells protect their genomes against one of the most toxic forms of DNA damage."
Publication details: Yerkin Dunbayev, Yen-Ju Chen, Lorenzo Sassi, Eun A Lee, Jae Sun Ra, Moonjung Choi, Anirban Mukherjee, Karen M Vasquez, Vincenzo Costanzo, Peter Chi, Kei-ichi Takata, The DNA helicase HELQ promotes replication fork reversal in coordination with BRCA2- and FANCD2-mediated repair pathways, Nucleic Acids Research, Volume 54, Issue 8, 8 May 2026, gkag332, https://doi.org/10.1093/nar/gkag332
