Chromodomain helicase DNA-binding protein 4 (CHD4) regulates homologous recombination DNA repair, and its deficiency sensitizes cells to poly(ADP-ribose) polymerase (PARP) inhibitor treatment.
To ensure genome stability, cells have evolved a robust defense mechanism to detect, signal, and repair damaged DNA that is generated by exogenous stressors such as ionizing radiation, endogenous stressors such as free radicals, or normal physiological processes such as DNA replication. Homologous recombination (HR) repair is a critical pathway of repairing DNA double strand breaks, and it plays an essential role in maintaining genomic integrity. Previous studies have shown that BRIT1, also known as MCPH1, is a key regulator of HR repair. Here, we report that chromodomain helicase DNA-binding protein 4 (CHD4) is a novel BRIT1 binding partner that regulates the HR repair process. The BRCA1 C-terminal domains of BRIT1 are required for its interaction with CHD4. Depletion of CHD4 and overexpression of the ATPase-dead form of CHD4 impairs the recruitment of BRIT1 to the DNA damage lesions. As a functional consequence, CHD4 deficiency sensitizes cells to double strand break-inducing agents, reduces the recruitment of HR repair factor BRCA1, and impairs HR repair efficiency. We further demonstrate that CHD4-depleted cells are more sensitive to poly(ADP-ribose) polymerase inhibitor treatment. In response to DNA damage induced by poly(ADP-ribose) polymerase inhibitors, CHD4 deficiency impairs the recruitment of DNA repair proteins BRIT1, BRCA1, and replication protein A at early steps of HR repair. Taken together, our findings identify an important role of CHD4 in controlling HR repair to maintain genome stability and establish the potential therapeutic implications of targeting CHD4 deficiency in tumors.
Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.
Mei-Ren
MR
Pan
Hui-Ju
HJ
Hsieh
Hui
H
Dai
Wen-Chun
WC
Hung
Kaiyi
K
Li
Guang
G
Peng
Shiaw-Yih
SY
Lin
D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D019313:BRCA1 Protein / Q000378:metabolism; D001940:Breast / Q000166:cytology; D001943:Breast Neoplasms; D018797:Cell Cycle Proteins; D002460:Cell Line; D002843:Chromatin / Q000502:physiology; D003598:Cytoskeletal Proteins; D004249:DNA Damage / Q000502:physiology; D004260:DNA Repair / Q000502:physiology*; D005260:Female; D059765:Homologous Recombination / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051716:Replication Protein A / Q000378:metabolism
D001324:Autoantigens; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C115323:CHD4 protein, human; D018797:Cell Cycle Proteins; D002843:Chromatin; D003598:Cytoskeletal Proteins; C460645:MCPH1 protein, human; D009419:Nerve Tissue Proteins; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; C497167:RPA1 protein, human; D051716:Replication Protein A; D011064:Poly Adenosine Diphosphate Ribose; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; C531550:olaparib