The 53BP1-dependent end-joining pathway plays a critical role in double strand 
break repair and is uniquely responsible for cellular sensitivity to 
poly(ADP-ribose) polymerase inhibitors (PARPi) in BRCA1-deficient cancers. We 
and others have investigated the downstream effectors of 53BP1, including 
replication timing regulatory factor 1 (RIF1) and Pax transactivation 
domain-interacting protein (PTIP), in the past few years to elucidate how loss 
of the 53BP1-dependent repair pathway results in PARPi resistance in BRCA1 
patients. However, questions regarding the upstream regulation of the 53BP1 
pathway remain unanswered. In this study, we identified the Tudor-interacting 
repair regulator (TIRR) that specifically associates with the ionizing 
radiation-induced foci formation region of 53BP1. 53BP1 and TIRR form a stable 
complex, which is required for their expression. Moreover, the 53BP1-TIRR 
complex dissociates after DNA damage, and this dissociation may be ataxia 
telangiectasia mutated-dependent. Similar to 53BP1, loss of TIRR restores PARPi 
resistance in BRCA1-deficient cells. Collectively, our data identified a novel 
53BP1-TIRR complex in DNA damage response. TIRR may play both positive and 
negative roles in 53BP1 regulation. On the one hand, it stabilizes 53BP1 and 
thus positively regulates 53BP1. On the other hand, its association with 53BP1 
prevents 53BP1 localization to sites of DNA damage, and thus TIRR is also an 
inhibitor of 53BP1.