Nucleic acids research · 2025
The chromatin regulator HELLS mediates SSB repair and responses to DNA alkylation damage.
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Joseph Joyous T, Wright Christine M, Peixoto Estanislao, Shibata Etsuko, Khan Asad, Li Yong, Neidigk Jason S Romero, Chen Bo-Ruei, Tufail Saba, Mujawar Aaiyas Abdulhamid, Decker Olivia, Kadali Krishna Reethika, Imtiaz Azait, Jones Brianna A, Zhang Yanfeng, Gradilone Sergio A, Lewis Zachary A, Contreras-Galindo Rafael, Sen Arko, Dutta Anindya, Czaja Wioletta
Аннотация
The SNF2 family chromatin remodeler HELLS has emerged as an important regulator of cell proliferation, genome stability, and several cancer pathways. Significant upregulation of HELLS has been reported in 33 human cancer types. While HELLS has been implicated in DNA damage response, its function in DNA repair is poorly understood. Here, we report a new regulatory link between HELLS and single-strand break (SSB) repair in cellular responses to DNA alkylation damage. We found that loss of HELLS impairs SSB repair and selectively sensitizes cells to DNA alkylating agents and PARP inhibitors (PARPi). Our data reveal non-epistatic interactions between HELLS and PARP1 and suggest that HELLS functionally compensates for PARP1 deficiency in promoting cell survival in response to DNA alkylation damage. Furthermore, we found that HELLS is co-expressed with PARP1 in cancer cells, and its loss is synthetic lethal with homologous recombination deficiency (HRD). This work unveils new functions of HELLS in modulating SSB repair and responses to clinically relevant DNA alkylation damage, thus offering new insights into the potential therapeutic value of targeting HELLS in cancer.