TY - JOUR
T1 - The chromatin regulator HELLS mediates SSB repair and responses to DNA alkylation damage
AU - Joseph, Joyous T.
AU - Wright, Christine M.
AU - Peixoto, Estanislao
AU - Shibata, Etsuko
AU - Khan, Asad
AU - Li, Yong
AU - Neidigk, Jason S.Romero
AU - Chen, Bo Ruei
AU - Tufail, Saba
AU - Mujawar, Aaiyas Abdulhamid
AU - Decker, Olivia
AU - Kadali, Krishna Reethika
AU - Imtiaz, Azait
AU - Jones, Brianna A.
AU - Zhang, Yanfeng
AU - Gradilone, Sergio A.
AU - Lewis, Zachary A.
AU - Contreras-Galindo, Rafael
AU - Sen, Arko
AU - Dutta, Anindya
AU - Czaja, Wioletta
N1 - Publisher Copyright:
© The Author(s) 2025. Published by Oxford University Press.
PY - 2025/12/11
Y1 - 2025/12/11
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105022911741
U2 - 10.1093/nar/gkaf1201
DO - 10.1093/nar/gkaf1201
M3 - Article
C2 - 41297801
AN - SCOPUS:105022911741
SN - 0305-1048
VL - 53
JO - Nucleic acids research
JF - Nucleic acids research
IS - 22
M1 - gkaf1201
ER -