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.